Scholars@Duke
Richard Gerald Brennan

Richard Gerald Brennan

James B. Duke Distinguished Professor of Biochemistry
Biochemistry

Selected Publications

Inhibitors of trehalose-6-phosphate synthase activity in fungal pathogens compromise thermal tolerance pathways.

Journal Article mBio · October 8, 2025 Infections caused by fungal pathogens such as Candida and Cryptococcus are associated with high mortality rates, partly due to limitations in the current antifungal arsenal. This highlights the need for antifungal drug targets with novel mechanisms of acti ... Full text Link to item Cite

A single amino acid in the Salmonella effector SarA/SteE triggers supraphysiological activation of STAT3 for anti-inflammatory gene expression.

Journal Article Cell Rep · April 22, 2025 Salmonella causes ∼1 million cases of gastroenteritis annually in the United States. Critical to virulence are secreted effectors that reprogram host functions. We previously discovered the effector SarA facilitates phosphorylation of STAT3, inducing expre ... Full text Link to item Cite

Structures of trehalose-6-phosphate synthase, Tps1, from the fungal pathogen Cryptococcus neoformans: A target for antifungals.

Journal Article Proc Natl Acad Sci U S A · August 6, 2024 Invasive fungal diseases are a major threat to human health, resulting in more than 1.5 million annual deaths worldwide. The arsenal of antifungal therapeutics remains limited and is in dire need of drugs that target additional biosynthetic pathways that a ... Full text Link to item Cite

How c-di-GMP controls progression through the Streptomyces life cycle.

Journal Article Curr Opin Microbiol · August 2024 Members of the antibiotic-producing bacterial genus Streptomyces undergo a complex developmental life cycle that culminates in the production of spores. Central to control of this cell differentiation process is signaling through the second messenger 3', 5 ... Full text Link to item Cite

Hormonal steroids induce multidrug resistance and stress response genes in Neisseria gonorrhoeae by binding to MtrR.

Journal Article Nat Commun · February 7, 2024 Transcriptional regulator MtrR inhibits the expression of the multidrug efflux pump operon mtrCDE in the pathogenic bacterium Neisseria gonorrhoeae. Here, we show that MtrR binds the hormonal steroids progesterone, β-estradiol, and testosterone, which are ... Full text Link to item Cite

Hormonal steroids bind the Neisseria gonorrhoeae multidrug resistance regulator, MtrR, to induce a multidrug binding efflux pump and stress-response sigma factor.

Journal Article bioRxiv · June 13, 2023 Overexpression of the multidrug efflux pump MtrCDE, a critical factor of multidrug-resistance in Neisseria gonorrhoeae , the causative agent of gonorrheae, is repressed by the transcriptional regulator, MtrR (multiple transferable resistance repressor). He ... Full text Link to item Cite

Single-cell genome-wide association reveals that a nonsynonymous variant in ERAP1 confers increased susceptibility to influenza virus.

Journal Article Cell Genom · November 9, 2022 During pandemics, individuals exhibit differences in risk and clinical outcomes. Here, we developed single-cell high-throughput human in vitro susceptibility testing (scHi-HOST), a method for rapidly identifying genetic variants that confer resistance and ... Full text Link to item Cite

Molecular dissection of the glutamine synthetase-GlnR nitrogen regulatory circuitry in Gram-positive bacteria.

Journal Issue Nat Commun · July 1, 2022 How bacteria sense and respond to nitrogen levels are central questions in microbial physiology. In Gram-positive bacteria, nitrogen homeostasis is controlled by an operon encoding glutamine synthetase (GS), a dodecameric machine that assimilates ammonium ... Full text Link to item Cite

The nucleotide messenger (p)ppGpp is an anti-inducer of the purine synthesis transcription regulator PurR in Bacillus.

Journal Article Nucleic Acids Res · January 25, 2022 The nucleotide messenger (p)ppGpp allows bacteria to adapt to fluctuating environments by reprogramming the transcriptome. Despite its well-recognized role in gene regulation, (p)ppGpp is only known to directly affect transcription in Proteobacteria by bin ... Full text Link to item Cite

Evolution of a σ-(c-di-GMP)-anti-σ switch.

Journal Article Proc Natl Acad Sci U S A · July 27, 2021 Filamentous actinobacteria of the genus Streptomyces have a complex lifecycle involving the differentiation of reproductive aerial hyphae into spores. We recently showed c-di-GMP controls this transition by arming a unique anti-σ, RsiG, to bind the sporula ... Full text Link to item Cite

Structures of Neisseria gonorrhoeae MtrR-operator complexes reveal molecular mechanisms of DNA recognition and antibiotic resistance-conferring clinical mutations.

Journal Article Nucleic Acids Res · April 19, 2021 Mutations within the mtrR gene are commonly found amongst multidrug resistant clinical isolates of Neisseria gonorrhoeae, which has been labelled a superbug by the Centers for Disease Control and Prevention. These mutations appear to contribute to antibiot ... Full text Link to item Cite

Structural Basis for Virulence Activation of Francisella tularensis.

Journal Article Mol Cell · January 7, 2021 The bacterium Francisella tularensis (Ft) is one of the most infectious agents known. Ft virulence is controlled by a unique combination of transcription regulators: the MglA-SspA heterodimer, PigR, and the stress signal, ppGpp. MglA-SspA assembles with th ... Full text Link to item Cite

Evolution of a o-(c-di-GMP)-anti-o switch

Journal Article PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA · 2021 Full text Cite

Optimization of a Noncanonical Anti-infective: Interrogation of the Target Binding Pocket for a Small-Molecule Inhibitor of Escherichia coli Polysaccharide Capsule Expression.

Journal Article Antimicrob Agents Chemother · December 16, 2020 We previously identified a small-molecule inhibitor of capsule biogenesis (designated DU011) and identified its target as MprA, a MarR family transcriptional repressor of multidrug efflux pumps. Unlike other proposed MprA ligands, such as salicylate and 2, ... Full text Link to item Cite

When is a transcription factor a NAP?

Journal Article Curr Opin Microbiol · June 2020 Proteins that regulate transcription often also play an architectural role in the genome. Thus, it has been difficult to define with precision the distinctions between transcription factors and nucleoid-associated proteins (NAPs). Anachronistic description ... Full text Link to item Cite

Crystal structure of an Escherichia coli Hfq Core (residues 2-69)-DNA complex reveals multifunctional nucleic acid binding sites.

Journal Article Nucleic Acids Res · April 17, 2020 Hfq regulates bacterial gene expression post-transcriptionally by binding small RNAs and their target mRNAs, facilitating sRNA-mRNA annealing, typically resulting in translation inhibition and RNA turnover. Hfq is also found in the nucleoid and binds doubl ... Full text Link to item Cite

MarR family proteins are important regulators of clinically relevant antibiotic resistance.

Journal Article Protein Sci · March 2020 There has been a rapid spread of multidrug-resistant (MDR) bacteria across the world. MDR efflux transporters are an important mechanism of antibiotic resistance in many pathogens among both Gram positive and Gram negative bacteria. These pumps can recogni ... Full text Link to item Cite

c-di-GMP Arms an Anti-σ to Control Progression of Multicellular Differentiation in Streptomyces.

Journal Article Mol Cell · February 6, 2020 Streptomyces are our primary source of antibiotics, produced concomitantly with the transition from vegetative growth to sporulation in a complex developmental life cycle. We previously showed that the signaling molecule c-di-GMP binds BldD, a master repre ... Full text Link to item Cite

The Salmonella Secreted Effector SarA/SteE Mimics Cytokine Receptor Signaling to Activate STAT3.

Journal Article Cell Host Microbe · January 8, 2020 Bacteria masterfully co-opt and subvert host signal transduction. As a paradigmatic example, Salmonella uses two type-3 secretion systems to inject effector proteins that facilitate Salmonella entry, establishment of an intracellular niche, and modulation ... Full text Link to item Cite

Structural, Biochemical, and In Vivo Characterization of MtrR-Mediated Resistance to Innate Antimicrobials by the Human Pathogen Neisseria gonorrhoeae.

Journal Article J Bacteriol · October 15, 2019 Neisseria gonorrhoeae responds to host-derived antimicrobials by inducing the expression of the mtrCDE-encoded multidrug efflux pump, which expels microbicides, such as bile salts, fatty acids, and multiple extrinsically administered drugs, from the cell. ... Full text Link to item Cite

Control of meristem determinacy by trehalose 6-phosphate phosphatases is uncoupled from enzymatic activity.

Journal Article Nat Plants · April 2019 Meristem fate is regulated by trehalose 6-phosphate phosphatases (TPPs), but their mechanism of action remains mysterious. Loss of the maize TPPs RAMOSA3 and TPP4 leads to reduced meristem determinacy and more inflorescence branching. However, analysis of ... Full text Link to item Cite

The MerR-like protein BldC binds DNA direct repeats as cooperative multimers to regulate Streptomyces development.

Journal Article Nat Commun · March 19, 2018 Streptomycetes are notable for their complex life cycle and production of most clinically important antibiotics. A key factor that controls entry into development and the onset of antibiotic production is the 68-residue protein, BldC. BldC is a putative DN ... Full text Link to item Cite

Dissection of the molecular circuitry controlling virulence in Francisella tularensis.

Journal Article Genes Dev · August 1, 2017 Francisella tularensis, the etiological agent of tularemia, is one of the most infectious bacteria known. Because of its extreme pathogenicity, F. tularensis is classified as a category A bioweapon by the US government. F. tularensis virulence stems from g ... Full text Link to item Cite

Structural and In Vivo Studies on Trehalose-6-Phosphate Synthase from Pathogenic Fungi Provide Insights into Its Catalytic Mechanism, Biological Necessity, and Potential for Novel Antifungal Drug Design.

Journal Article mBio · July 25, 2017 The disaccharide trehalose is critical to the survival of pathogenic fungi in their human host. Trehalose-6-phosphate synthase (Tps1) catalyzes the first step of trehalose biosynthesis in fungi. Here, we report the first structures of eukaryotic Tps1s in c ... Full text Link to item Cite

The Streptomyces master regulator BldD binds c-di-GMP sequentially to create a functional BldD2-(c-di-GMP)4 complex.

Journal Article Nucleic Acids Res · June 20, 2017 Streptomyces are ubiquitous soil bacteria that undergo a complex developmental transition coinciding with their production of antibiotics. This transition is controlled by binding of a novel tetrameric form of the second messenger, 3΄-5΄ cyclic diguanylic ... Full text Link to item Cite

Central Role of the Trehalose Biosynthesis Pathway in the Pathogenesis of Human Fungal Infections: Opportunities and Challenges for Therapeutic Development.

Journal Article Microbiol Mol Biol Rev · June 2017 Invasive fungal infections cause significant morbidity and mortality in part due to a limited antifungal drug arsenal. One therapeutic challenge faced by clinicians is the significant host toxicity associated with antifungal drugs. Another challenge is the ... Full text Link to item Cite

Trehalose pathway as an antifungal target.

Journal Article Virulence · February 17, 2017 With an increasing immunocompromised population which is linked to invasive fungal infections, it is clear that our present 3 classes of antifungal agents may not be sufficient to provide optimal management to these fragile patients. Furthermore, with wide ... Full text Link to item Cite

Structures of trehalose-6-phosphate phosphatase from pathogenic fungi reveal the mechanisms of substrate recognition and catalysis.

Journal Article Proc Natl Acad Sci U S A · June 28, 2016 Trehalose is a disaccharide essential for the survival and virulence of pathogenic fungi. The biosynthesis of trehalose requires trehalose-6-phosphate synthase, Tps1, and trehalose-6-phosphate phosphatase, Tps2. Here, we report the structures of the N-term ... Full text Link to item Cite

HipBA-promoter structures reveal the basis of heritable multidrug tolerance.

Journal Article Nature · August 6, 2015 Multidrug tolerance is largely responsible for chronic infections and caused by a small population of dormant cells called persisters. Selection for survival in the presence of antibiotics produced the first genetic link to multidrug tolerance: a mutant in ... Full text Link to item Cite

Mutations within the mepA operator affect binding of the MepR regulatory protein and its induction by MepA substrates in Staphylococcus aureus.

Journal Article J Bacteriol · March 2015 The expression of mepA, encoding the Staphylococcus aureus MepA multidrug efflux protein, is repressed by the MarR homologue MepR. Repression occurs through binding of two MepR dimers to an operator with two homologous and closely approximated pseudopalind ... Full text Link to item Cite

Glutathione activates virulence gene expression of an intracellular pathogen.

Journal Article Nature · January 8, 2015 Intracellular pathogens are responsible for much of the world-wide morbidity and mortality due to infectious diseases. To colonize their hosts successfully, pathogens must sense their environment and regulate virulence gene expression appropriately. Accord ... Full text Link to item Cite

Structural and Biochemical Characterization of the Francisella tularensis Pathogenicity Regulator, Macrophage Locus Protein A (MglA).

Journal Article PLoS One · 2015 Francisella tularensis is one of the most infectious bacteria known and is the etiologic agent of tularemia. Francisella virulence arises from a 33 kilobase (Kb) pathogenicity island (FPI) that is regulated by the macrophage locus protein A (MglA) and the ... Full text Link to item Cite

Recognition of U-rich RNA by Hfq from the Gram-positive pathogen Listeria monocytogenes.

Journal Article RNA · October 2014 Hfq is a post-transcriptional regulator that binds U- and A-rich regions of sRNAs and their target mRNAs to stimulate their annealing in order to effect translation regulation and, often, to alter their stability. The functional importance of Hfq and its R ... Full text Link to item Cite

Tetrameric c-di-GMP mediates effective transcription factor dimerization to control Streptomyces development.

Journal Article Cell · August 28, 2014 The cyclic dinucleotide c-di-GMP is a signaling molecule with diverse functions in cellular physiology. Here, we report that c-di-GMP can assemble into a tetramer that mediates the effective dimerization of a transcription factor, BldD, which controls the ... Full text Link to item Cite

Structural mechanism of transcription regulation of the Staphylococcus aureus multidrug efflux operon mepRA by the MarR family repressor MepR.

Journal Article Nucleic Acids Res · February 2014 The multidrug efflux pump MepA is a major contributor to multidrug resistance in Staphylococcus aureus. MepR, a member of the multiple antibiotic resistance regulator (MarR) family, represses mepA and its own gene. Here, we report the structure of a MepR-m ... Full text Link to item Cite

Mapping Hfq-RNA interaction surfaces using tryptophan fluorescence quenching.

Journal Article Nucleic Acids Res · February 2014 Hfq is a posttranscriptional riboregulator and RNA chaperone that binds small RNAs and target mRNAs to effect their annealing and message-specific regulation in response to environmental stressors. Structures of Hfq-RNA complexes indicate that U-rich seque ... Full text Link to item Cite

The molecular mechanisms of allosteric mutations impairing MepR repressor function in multidrug-resistant strains of Staphylococcus aureus.

Journal Article mBio · August 27, 2013 UNLABELLED: Overexpression of the Staphylococcus aureus multidrug efflux pump MepA confers resistance to a wide variety of antimicrobials. mepA expression is controlled by MarR family member MepR, which represses mepA and autorepresses its own production. ... Full text Link to item Cite

Functional consequences of substitution mutations in MepR, a repressor of the Staphylococcus aureus MepA multidrug efflux pump gene.

Journal Article J Bacteriol · August 2013 The expression of mepA, encoding the Staphylococcus aureus MepA multidrug efflux protein, is repressed by the MarR homologue MepR. MepR dimers bind differently to operators upstream of mepR and mepA, with affinity being greatest at the mepA operator. MepR ... Full text Link to item Cite

Serine substitution of proline at codon 151 of TP53 confers gain of function activity leading to anoikis resistance and tumor progression of head and neck cancer cells.

Journal Article Laryngoscope · June 2013 OBJECTIVES/HYPOTHESIS: Mutation of the TP53 gene occurs in more than half of cases of head and neck squamous cell carcinoma (HNSCC). However, little is known about how specific TP53 mutations affect tumor progression. The objective of this study is to dete ... Full text Link to item Cite

Studies of IscR reveal a unique mechanism for metal-dependent regulation of DNA binding specificity

Journal Article Nature Structural and Molecular Biology · 2013 IscR from Escherichia coli is an unusual metalloregulator in that both apo and iron sulfur (Fe-S)-IscR regulate transcription and exhibit different DNA binding specificities. Here, we report structural and biochemical studies of IscR suggesting that remode ... Full text Cite

Structural mechanism of Staphylococcus aureus Hfq binding to an RNA A-tract.

Journal Article Nucleic Acids Res · November 2012 Hfq is a post-transcriptional regulator that plays a key role in bacterial gene expression by binding AU-rich sequences and A-tracts to facilitate the annealing of sRNAs to target mRNAs and to affect RNA stability. To understand how Hfq from the Gram-posit ... Full text Link to item Cite

Role of unusual P loop ejection and autophosphorylation in HipA-mediated persistence and multidrug tolerance.

Journal Article Cell Rep · September 27, 2012 HipA is a bacterial serine/threonine protein kinase that phosphorylates targets, bringing about persistence and multidrug tolerance. Autophosphorylation of residue Ser150 is a critical regulatory mechanism of HipA function. Intriguingly, Ser150 is not loca ... Full text Link to item Cite

GQ-16, a novel peroxisome proliferator-activated receptor γ (PPARγ) ligand, promotes insulin sensitization without weight gain.

Journal Article J Biol Chem · August 10, 2012 The recent discovery that peroxisome proliferator-activated receptor γ (PPARγ) targeted anti-diabetic drugs function by inhibiting Cdk5-mediated phosphorylation of the receptor has provided a new viewpoint to evaluate and perhaps develop improved insulin-s ... Full text Link to item Cite

Regulation of the Escherichia coli HipBA toxin-antitoxin system by proteolysis.

Journal Article PLoS One · 2012 Bacterial populations produce antibiotic-tolerant persister cells. A number of recent studies point to the involvement of toxin/antitoxin (TA) modules in persister formation. hipBA is a type II TA module that codes for the HipB antitoxin and the HipA toxin ... Full text Link to item Cite

The crystal structure of the TetR family transcriptional repressor SimR bound to DNA and the role of a flexible N-terminal extension in minor groove binding.

Journal Article Nucleic Acids Res · November 2011 SimR, a TetR-family transcriptional regulator (TFR), controls the export of simocyclinone, a potent DNA gyrase inhibitor made by Streptomyces antibioticus. Simocyclinone is exported by a specific efflux pump, SimX and the transcription of simX is repressed ... Full text Link to item Cite

Distinct single amino acid replacements in the control of virulence regulator protein differentially impact streptococcal pathogenesis.

Journal Article PLoS Pathog · October 2011 Sequencing of invasive strains of group A streptococci (GAS) has revealed a diverse array of single nucleotide polymorphisms in the gene encoding the control of virulence regulator (CovR) protein. However, there is limited information regarding the molecul ... Full text Link to item Cite

Niche-specific contribution to streptococcal virulence of a MalR-regulated carbohydrate binding protein.

Journal Article Mol Microbiol · July 2011 Low G+C Gram-positive bacteria typically contain multiple LacI/GalR regulator family members, which often have highly similar amino-terminal DNA binding domains, suggesting significant overlap in target DNA sequences. The LacI/GalR family regulator catabol ... Full text Link to item Cite

Structures of carbon catabolite protein A-(HPr-Ser46-P) bound to diverse catabolite response element sites reveal the basis for high-affinity binding to degenerate DNA operators.

Journal Article Nucleic Acids Res · April 2011 In Gram-positive bacteria, carbon catabolite protein A (CcpA) is the master regulator of carbon catabolite control, which ensures optimal energy usage under diverse conditions. Unlike other LacI-GalR proteins, CcpA is activated for DNA binding by first for ... Full text Link to item Cite

A single acidic residue can guide binding site selection but does not govern QacR cationic-drug affinity.

Journal Article PLoS One · January 17, 2011 Structures of the multidrug-binding repressor protein QacR with monovalent and bivalent cationic drugs revealed that the carboxylate side-chains of E90 and E120 were proximal to the positively charged nitrogens of the ligands ethidium, malachite green and ... Full text Link to item Cite

Differential neural responses to food images in women with bulimia versus anorexia nervosa.

Journal Article PLoS One · 2011 BACKGROUND: Previous fMRI studies show that women with eating disorders (ED) have differential neural activation to viewing food images. However, despite clinical differences in their responses to food, differential neural activation to thinking about eati ... Full text Link to item Cite

Xenopus Kazrin interacts with ARVCF-catenin, spectrin and p190B RhoGAP, and modulates RhoA activity and epithelial integrity.

Journal Article J Cell Sci · December 1, 2010 In common with other p120-catenin subfamily members, Xenopus ARVCF (xARVCF) binds cadherin cytoplasmic domains to enhance cadherin metabolic stability or, when dissociated, modulates Rho-family GTPases. We report here that xARVCF binds and is stabilized by ... Full text Link to item Cite

C-terminally truncated derivatives of Escherichia coli Hfq are proficient in riboregulation.

Journal Article J Mol Biol · November 26, 2010 The prokaryotic Sm-like protein Hfq plays an essential role in the stability and function of trans-encoded small regulatory RNAs in enterobacteria that function in posttranscriptional control by base-pairing with cognate target mRNAs. Hfq associates with b ... Full text Link to item Cite

Conformational plasticity of the coiled-coil domain of BmrR is required for bmr operator binding: the structure of unliganded BmrR.

Journal Article J Mol Biol · April 30, 2010 The multidrug-binding transcription regulator BmrR from Bacillus subtilis is a MerR family member that binds to a wide array of cationic lipophilic toxins to activate the transcription of the multidrug efflux pump gene bmr. Transcription activation from th ... Full text Link to item Cite

A combination of independent transcriptional regulators shapes bacterial virulence gene expression during infection.

Journal Article PLoS Pathog · March 19, 2010 Transcriptional regulatory networks are fundamental to how microbes alter gene expression in response to environmental stimuli, thereby playing a critical role in bacterial pathogenesis. However, understanding how bacterial transcriptional regulatory netwo ... Full text Link to item Cite

Promoter recognition by a complex of Spx and the C-terminal domain of the RNA polymerase alpha subunit.

Journal Article PLoS One · January 13, 2010 BACKGROUND: Spx, an ArsC (arsenate reductase) family member, is a global transcriptional regulator of the microbial stress response and is highly conserved amongst Gram-positive bacteria. Bacillus subtilis Spx protein exerts positive and negative control o ... Full text Link to item Cite

Promoter recognition by a complex of Spx and the C-terminal domain of the RNA polymerase α subunit

Journal Article PLoS ONE · 2010 Background: Spx, an ArsC (arsenate reductase) family member, is a global transcriptional regulator of the microbial stress response and is highly conserved amongst Gram-positive bacteria. Bacillus subtilis Spx protein exerts positive and negative control o ... Full text Cite

Structure of Escherichia coli Hfq bound to polyriboadenylate RNA.

Journal Article Proc Natl Acad Sci U S A · November 17, 2009 Hfq is a small, highly abundant hexameric protein that is found in many bacteria and plays a critical role in mRNA expression and RNA stability. As an "RNA chaperone," Hfq binds AU-rich sequences and facilitates the trans annealing of small RNAs (sRNAs) to ... Full text Link to item Cite

Characterization and structure of the manganese-responsive transcriptional regulator ScaR.

Journal Article Biochemistry · November 3, 2009 The streptococcal coaggregation regulator (ScaR) of Streptococcus gordonii is a manganese-dependent transcriptional regulator. When intracellular manganese concentrations become elevated, ScaR represses transcription of the scaCBA operon, which encodes a m ... Full text Link to item Cite

Optimized production and analysis of the staphylococcal multidrug efflux protein QacA.

Journal Article Protein Expr Purif · April 2009 The plasmid-encoded QacA multidrug transport protein confers high-level resistance to a range of commonly used antimicrobials and is carried by widespread clinical strains of the human pathogen Staphylococcus aureus making it a potential target for future ... Full text Link to item Cite

Structural and biochemical characterization of MepR, a multidrug binding transcription regulator of the Staphylococcus aureus multidrug efflux pump MepA.

Journal Article Nucleic Acids Res · March 2009 MepR is a multidrug binding transcription regulator that represses expression of the Staphylococcus aureus multidrug efflux pump gene, mepA, as well as its own gene. MepR is induced by multiple cationic toxins, which are also substrates of MepA. In order t ... Full text Link to item Cite

Molecular mechanisms of HipA-mediated multidrug tolerance and its neutralization by HipB.

Journal Article Science · January 16, 2009 Bacterial multidrug tolerance is largely responsible for the inability of antibiotics to eradicate infections and is caused by a small population of dormant bacteria called persisters. HipA is a critical Escherichia coli persistence factor that is normally ... Full text Link to item Cite

Structures of BmrR-drug complexes reveal a rigid multidrug binding pocket and transcription activation through tyrosine expulsion.

Journal Article J Biol Chem · September 26, 2008 BmrR is a member of the MerR family and a multidrug binding transcription factor that up-regulates the expression of the bmr multidrug efflux transporter gene in response to myriad lipophilic cationic compounds. The structural mechanism by which BmrR binds ... Full text Link to item Cite

QacR-cation recognition is mediated by a redundancy of residues capable of charge neutralization.

Journal Article Biochemistry · August 5, 2008 The Staphylococcus aureus multidrug binding protein QacR binds to a broad spectrum of structurally dissimilar cationic, lipophilic drugs. Our previous structural analyses suggested that five QacR glutamic acid residues are critical for charge neutralizatio ... Full text Link to item Cite

Molecular characterization of group A Streptococcus maltodextrin catabolism and its role in pharyngitis.

Journal Article Mol Microbiol · July 2008 We previously demonstrated that the cell-surface lipoprotein MalE contributes to GAS maltose/maltodextrin utilization, but MalE inactivation does not completely abrogate GAS catabolism of maltose or maltotriose. Using a genome-wide approach, we identified ... Full text Link to item Cite

A direct link between carbohydrate utilization and virulence in the major human pathogen group A Streptococcus.

Journal Article Proc Natl Acad Sci U S A · February 5, 2008 Although central to pathogenesis, the molecular mechanisms used by microbes to regulate virulence factor production in specific environments during host-pathogen interaction are poorly defined. Several recent ex vivo and in vivo studies have found that the ... Full text Link to item Cite

Chromatin-associated HMG-17 is a major regulator of homeodomain transcription factor activity modulated by Wnt/beta-catenin signaling.

Journal Article Nucleic Acids Res · February 2008 Homeodomain (HD) transcriptional activities are tightly regulated during embryogenesis and require protein interactions for their spatial and temporal activation. The chromatin-associated high mobility group protein (HMG-17) is associated with transcriptio ... Full text Link to item Cite

Structural mechanism of organic hydroperoxide induction of the transcription regulator OhrR.

Journal Article Mol Cell · November 30, 2007 The Xanthomonas campestris transcription regulator OhrR contains a reactive cysteine residue (C22) that upon oxidation by organic hydroperoxides (OHPs) forms an intersubunit disulphide bond with residue C127'. Such modification induces the expression of a ... Full text Link to item Cite

Multidrug-binding transcription factor QacR binds the bivalent aromatic diamidines DB75 and DB359 in multiple positions.

Journal Article J Am Chem Soc · July 4, 2007 Staphylococcus aureus QacR is a multidrug-binding transcription repressor. Crystal structures of multiple QacR-drug complexes reveal that these toxins bind in a large pocket, which is composed of smaller overlapping "minipockets". Stacking, van der Waals, ... Full text Link to item Cite

Structural mechanism for the fine-tuning of CcpA function by the small molecule effectors glucose 6-phosphate and fructose 1,6-bisphosphate.

Journal Article J Mol Biol · May 11, 2007 In Gram-positive bacteria, carbon catabolite regulation (CCR) is mediated by the carbon catabolite control protein A (CcpA), a member of the LacI-GalR family of transcription regulators. Unlike other LacI-GalR proteins, CcpA is activated to bind DNA by bin ... Full text Link to item Cite

Hfq structure, function and ligand binding.

Journal Article Curr Opin Microbiol · April 2007 Recent studies on Hfq have provided a deeper understanding of the multiple functions of this pleiotropic post-transcriptional regulator. Insights into the mechanism of Hfq action have come from a variety of approaches. A key finding was the characterizatio ... Full text Link to item Cite

The conformations of the manganese transport regulator of Bacillus subtilis in its metal-free state.

Journal Article J Mol Biol · February 2, 2007 The manganese transport regulator (MntR) from Bacillus subtilis binds cognate DNA sequences in response to elevated manganese concentrations. MntR functions as a homodimer that binds two manganese ions per subunit. Metal binding takes place at the interfac ... Full text Link to item Cite

Structure of FitAB from Neisseria gonorrhoeae bound to DNA reveals a tetramer of toxin-antitoxin heterodimers containing pin domains and ribbon-helix-helix motifs.

Journal Article J Biol Chem · December 8, 2006 Neisseria gonorrhoeae is a sexually transmitted pathogen that initiates infections in humans by adhering to the mucosal epithelium of the urogenital tract. The bacterium then enters the apical region of the cell and traffics across the cell to exit into th ... Full text Link to item Cite

Structural basis for the metal-selective activation of the manganese transport regulator of Bacillus subtilis.

Journal Article Biochemistry · March 21, 2006 The manganese transport regulator (MntR) of Bacillus subtilis is activated by Mn(2+) to repress transcription of genes encoding transporters involved in the uptake of manganese. MntR is also strongly activated by cadmium, both in vivo and in vitro, but it ... Full text Link to item Cite

Phosphoprotein Crh-Ser46-P displays altered binding to CcpA to effect carbon catabolite regulation.

Journal Article J Biol Chem · March 10, 2006 In Gram-positive bacteria, the catabolite control protein A (CcpA) functions as the master transcriptional regulator of carbon catabolite repression/regulation (CCR). To effect CCR, CcpA binds a phosphoprotein, either HPr-Ser46-P or Crh-Ser46-P. Although C ... Full text Link to item Cite

Crystal structure of the Bacillus subtilis anti-alpha, global transcriptional regulator, Spx, in complex with the alpha C-terminal domain of RNA polymerase.

Journal Article Proc Natl Acad Sci U S A · November 1, 2005 Spx, a global transcription regulator in Bacillus subtilis, interacts with the C-terminal domain of the alpha subunit (alphaCTD) of RNA polymerase to control gene expression under conditions of disulfide stress, which is sensed by disulfide bond formation ... Full text Link to item Cite

Structure of an OhrR-ohrA operator complex reveals the DNA binding mechanism of the MarR family.

Journal Article Mol Cell · October 7, 2005 The mechanisms by which Bacillus subtilis OhrR, a member of the MarR family of transcription regulators, binds the ohrA operator and is induced by oxidation of its lone cysteine residue by organic hydroperoxides to sulphenic acid are unknown. Here, we desc ... Full text Link to item Cite

Neisseria gonorrhoeae FitA interacts with FitB to bind DNA through its ribbon-helix-helix motif.

Journal Article Biochemistry · September 20, 2005 The fit locus, encoding two proteins, FitA and FitB, was identified in a genetic screen for Neisseria gonorrhoeae determinants that affect trafficking across polarized epithelial cells. To better understand how the locus may control these activities, we ha ... Full text Link to item Cite

Characterization of the multiple transferable resistance repressor, MtrR, from Neisseria gonorrhoeae.

Journal Article J Bacteriol · July 2005 MtrR represses expression of the Neisseria gonorrhoeae mtrCDE multidrug efflux transporter genes. MtrR displays salt-dependent DNA binding, a stoichiometry of two dimers per DNA site, and, for a protein that was expected to be essentially all helical, a hi ... Full text Link to item Cite

The TetR family of transcriptional repressors.

Journal Article Microbiol Mol Biol Rev · June 2005 We have developed a general profile for the proteins of the TetR family of repressors. The stretch that best defines the profile of this family is made up of 47 amino acid residues that correspond to the helix-turn-helix DNA binding motif and adjacent regi ... Full text Link to item Cite

Structural basis for allosteric control of the transcription regulator CcpA by the phosphoprotein HPr-Ser46-P.

Journal Article Cell · September 17, 2004 Carbon catabolite repression (CCR) is one of the most fundamental environmental-sensing mechanisms in bacteria and imparts competitive advantage by establishing priorities in carbon metabolism. In gram-positive bacteria, the master transcription regulator ... Full text Link to item Cite

Structural mechanism of the simultaneous binding of two drugs to a multidrug-binding protein.

Journal Article EMBO J · August 4, 2004 The structural basis of simultaneous binding of two or more different drugs by any multidrug-binding protein is unknown and also how this can lead to a noncompetitive, uncompetitive or cooperative binding mechanism. Here, we describe the crystal structure ... Full text Link to item Cite

The structural mechanism for transcription activation by MerR family member multidrug transporter activation, N terminus.

Journal Article J Biol Chem · May 7, 2004 Transcription regulators of the MerR family respond to myriad stress signals to activate sigma70/sigmaA-targeted genes, which contain suboptimal 19-bp spacers between their -35 and -10 promoter elements. The crystal structure of a BmrR-TPP(+)-DNA complex p ... Full text Link to item Cite

Crystal structures of QacR-diamidine complexes reveal additional multidrug-binding modes and a novel mechanism of drug charge neutralization.

Journal Article J Biol Chem · April 2, 2004 The Staphylococcus aureus multidrug-binding protein QacR represses transcription of the plasmid-encoded membrane protein QacA, a multidrug efflux transporter. QacR is induced by multiple structurally dissimilar monovalent and bivalent cationic lipophilic c ... Full text Link to item Cite

Structure of the manganese-bound manganese transport regulator of Bacillus subtilis.

Journal Article Nat Struct Biol · August 2003 The Bacillus subtilis manganese transport regulator, MntR, binds Mn2+ as an effector and is a repressor of transporters that import manganese. A member of the diphtheria toxin repressor (DtxR) family of metalloregulatory proteins, MntR exhibits selectivity ... Full text Link to item Cite

Deciphering the molecular basis of multidrug recognition: crystal structures of the Staphylococcus aureus multidrug binding transcription regulator QacR.

Journal Article Res Microbiol · March 2003 Multidrug transporters and their transcriptional regulators are key components of bacterial multidrug resistance (MDR). How these multidrug binding proteins can recognize such chemically disparate compounds represents a fascinating question from a structur ... Full text Link to item Cite

Crystal structure of HPr kinase/phosphatase from Mycoplasma pneumoniae.

Journal Article J Mol Biol · February 28, 2003 HPr kinase/phosphatase (HPrK/P) modifies serine 46 of histidine-containing protein (HPr), the phosphorylation state of which is the control point of carbon catabolite repression in low G+C Gram-positive bacteria. To understand the structural mechanism by w ... Full text Link to item Cite

Structural mechanisms of multidrug recognition and regulation by bacterial multidrug transcription factors.

Journal Article Mol Microbiol · August 2002 The increase in bacterial resistance to multiple drugs represents a serious and growing health risk. One component of multidrug resistance (MDR) is a group of multidrug transporters that are often regulated at the transcriptional level by repressors and/or ... Full text Link to item Cite

Structures of the pleiotropic translational regulator Hfq and an Hfq-RNA complex: a bacterial Sm-like protein.

Journal Article EMBO J · July 1, 2002 In prokaryotes, Hfq regulates translation by modulating the structure of numerous RNA molecules by binding preferentially to A/U-rich sequences. To elucidate the mechanisms of target recognition and translation regulation by Hfq, we determined the crystal ... Full text Link to item Cite

Kinetic mechanism of adenine phosphoribosyltransferase from Leishmania donovani.

Journal Article Biochemistry · March 26, 2002 Adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) catalyzes the reversible phosphoribosylation of adenine from alpha-D-5-phosphoribosyl-1-pyrophosphate (PRPP) to form AMP and PP(i). Three-dimensional structures of the dimeric APRT enzyme from Leishmania ... Full text Link to item Cite

Structural basis for cooperative DNA binding by two dimers of the multidrug-binding protein QacR.

Journal Article EMBO J · March 1, 2002 The Staphylococcus aureus multidrug-binding protein QacR represses transcription of the qacA multidrug transporter gene and is induced by multiple structurally dissimilar drugs. QacR is a member of the TetR/CamR family of transcriptional regulators, which ... Full text Link to item Cite

Crystallization, preliminary X-ray analysis and biophysical characterization of HPr kinase/phosphatase of Mycoplasma pneumoniae.

Journal Article Acta Crystallogr D Biol Crystallogr · March 2002 The Mycoplasma pneumoniae HPr kinase/phosphatase (HPrK/P) is a member of a large family of enzymes which are central to carbon regulation in Gram-positive bacteria. The full-length M. pneumonia HPrK/P was crystallized from solutions of polyethylene glycol ... Full text Link to item Cite

Prokaryotic transcription regulators: more than just the helix-turn-helix motif.

Journal Article Curr Opin Struct Biol · February 2002 Over the past two years, the structures of many prokaryotic transcriptional regulators have been solved, and several of them have revealed the structural mechanism of gene regulation. The crystal structure of BmrR-TPP-DNA reveals a novel mechanism of trans ... Full text Link to item Cite

Role of residue 147 in the gene regulatory function of the Escherichia coli purine repressor.

Journal Article Biochemistry · January 15, 2002 The crystal structures of corepressor-bound and free Escherichia coli purine repressor (PurR) have delineated the roles of several residues in corepressor binding and specificity and the intramolecular signal transduction (allosterism) of this LacI/GalR fa ... Full text Link to item Cite

The structural mechanism of GTP stabilized oligomerization and catalytic activation of the Toxoplasma gondii uracil phosphoribosyltransferase.

Journal Article Proc Natl Acad Sci U S A · January 8, 2002 Uracil phosphoribosyltransferase (UPRT) is a member of a large family of salvage and biosynthetic enzymes, the phosphoribosyltransferases, and catalyzes the transfer of ribose 5-phosphate from alpha-d-5-phosphoribosyl-1-pyrophosphate (PRPP) to the N1 nitro ... Full text Link to item Cite

Hfq: a bacterial Sm-like protein that mediates RNA-RNA interaction.

Journal Article Mol Cell · January 2002 The bacterial Hfq protein modulates the stability or the translation of mRNAs and has recently been shown to interact with small regulatory RNAs in E. coli. Here we show that Hfq belongs to the large family of Sm and Sm-like proteins: it contains a conserv ... Full text Link to item Cite

Crystal structure of MtaN, a global multidrug transporter gene activator.

Journal Article J Biol Chem · December 14, 2001 MtaN (Multidrug Transporter Activation, N terminus) is a constitutive, transcriptionally active 109-residue truncation mutant, which contains only the N-terminal DNA-binding and dimerization domains of MerR family member Mta. The 2.75 A resolution crystal ... Full text Link to item Cite

Structural mechanisms of QacR induction and multidrug recognition.

Journal Article Science · December 7, 2001 The Staphylococcus aureus multidrug binding protein QacR represses transcription of the qacA multidrug transporter gene and is induced by structurally diverse cationic lipophilic drugs. Here, we report the crystal structures of six QacR-drug complexes. Com ... Full text Link to item Cite

The staphylococcal QacR multidrug regulator binds a correctly spaced operator as a pair of dimers.

Journal Article J Bacteriol · December 2001 Expression of the Staphylococcus aureus plasmid-encoded QacA multidrug transporter is regulated by the divergently encoded QacR repressor protein. To circumvent the formation of disulfide-bonded degradation products, site-directed mutagenesis to replace th ... Full text Link to item Cite

The basic helix-loop-helix domain of the aryl hydrocarbon receptor nuclear transporter (ARNT) can oligomerize and bind E-box DNA specifically.

Journal Article J Biol Chem · November 2, 2001 The aryl hydrocarbon receptor nuclear transporter (ARNT) is a basic helix-loop-helix (bHLH) protein that contains a Per-Arnt-Sim (PAS) domain. ARNT heterodimerizes in vivo with other bHLH PAS proteins to regulate a number of cellular activities, but a phys ... Full text Link to item Cite

Consensus and variant cAMP-regulated enhancers have distinct CREB-binding properties.

Journal Article J Biol Chem · April 13, 2001 Recent determination of the cAMP response element-binding protein (CREB) basic leucine zipper (bZIP) consensus CRE crystal structure revealed key dimerization and DNA binding features that are conserved among members of the CREB/CREM/ATF-1 family of transc ... Full text Link to item Cite

Crystal structure of the transcription activator BmrR bound to DNA and a drug.

Journal Article Nature · January 18, 2001 The efflux of chemically diverse drugs by multidrug transporters that span the membrane is one mechanism of multidrug resistance in bacteria. The concentrations of many of these transporters are controlled by transcription regulators, such as BmrR in Bacil ... Full text Link to item Cite

Crystal structures of SarA, a pleiotropic regulator of virulence genes in S. aureus.

Journal Article Nature · January 11, 2001 Staphylococcus aureus is a major human pathogen, the potency of which can be attributed to the regulated expression of an impressive array of virulence determinants. A key pleiotropic transcriptional regulator of these virulence factors is SarA, which is e ... Full text Link to item Cite

Introduction: Multidrug resistance

Journal Article Seminars in Cell and Developmental Biology · January 1, 2001 Full text Cite

The structure of a CREB bZIP.somatostatin CRE complex reveals the basis for selective dimerization and divalent cation-enhanced DNA binding.

Journal Article J Biol Chem · November 10, 2000 The cAMP responsive element-binding protein (CREB) is central to second messenger regulated transcription. To elucidate the structural mechanisms of DNA binding and selective dimerization of CREB, we determined to 3.0 A resolution, the structure of the CRE ... Full text Link to item Cite

Characterization of the DNA- and metal-binding properties of Vibrio anguillarum fur reveals conservation of a structural Zn(2+) ion.

Journal Article J Bacteriol · November 2000 The ferric uptake regulator, Fur, represses iron uptake and siderophore biosynthetic genes under iron-replete conditions. Here we report in vitro solution studies on Vibrio anguillarum Fur binding to the consensus 19-bp Escherichia coli iron box in the pre ... Full text Link to item Cite

Crystallization and preliminary X-ray diffraction studies on the DNA-binding domain of the multidrug transporter activation protein (MtaN) from Bacillus subtilis.

Journal Article Acta Crystallogr D Biol Crystallogr · November 2000 The N-terminal DNA-binding domain of the multidrug transporter activation protein (MtaN) was crystallized by the hanging-drop vapour-diffusion method using lithium chloride as a precipitant. The crystals are orthorhombic and belong to the space group I2(1) ... Full text Link to item Cite

The structural basis of repertoire shift in an immune response to phosphocholine.

Journal Article J Exp Med · June 19, 2000 The immune response to phosphocholine (PC)-protein is characterized by a shift in antibody repertoire as the response progresses. This change in expressed gene combinations is accompanied by a shift in fine specificity toward the carrier, resulting in high ... Full text Link to item Cite

Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.

Journal Article J Mol Biol · May 19, 2000 Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the s ... Full text Link to item Cite

Recruitment of CREB binding protein is sufficient for CREB-mediated gene activation.

Journal Article Mol Cell Biol · March 2000 Phosphorylation of the transcription factor CREB leads to the recruitment of the coactivator, CREB binding protein (CBP). Recent studies have suggested that CBP recruitment is not sufficient for CREB function, however. We have identified a conserved protei ... Full text Link to item Cite

Crystal structures of Toxoplasma gondii adenosine kinase reveal a novel catalytic mechanism and prodrug binding.

Journal Article J Mol Biol · February 18, 2000 Adenosine kinase (AK) is a key purine metabolic enzyme from the opportunistic parasitic protozoan Toxoplasma gondii and belongs to the family of carbohydrate kinases that includes ribokinase. To understand the catalytic mechanism of AK, we determined the s ... Full text Link to item Cite

A structure-based mechanism for drug binding by multidrug transporters.

Journal Article Trends Biochem Sci · February 2000 Multidrug transporters bind chemically dissimilar, potentially cytotoxic compounds and remove them from the cell. How these transporters carry out either of these functions is unknown. On the basis of crystal structures of the multidrug-binding domain of t ... Full text Link to item Cite

Recognition of multiple drugs by a single protein: a trivial solution of an old paradox.

Journal Article Biochem Soc Trans · 2000 Multidrug-efflux transporters recognize scores of structurally dissimilar toxic compounds and expel them from cells. The broad chemical specificity of these transporters challenges some of the basic dogmas of biochemistry and remains unexplained. To unders ... Link to item Cite

The role of lysine 55 in determining the specificity of the purine repressor for its operators through minor groove interactions.

Journal Article J Mol Biol · August 13, 1999 The interaction of the dimeric Escherichia coli purine repressor (PurR) with its cognate sequences leads to a 45 degrees to 50 degrees kink at a central CpG base step towards the major groove, as dyad-related leucine side-chains interdigitate between these ... Full text Link to item Cite

Crystal structures of adenine phosphoribosyltransferase from Leishmania donovani.

Journal Article EMBO J · July 1, 1999 The enzyme adenine phosphoribosyltransferase (APRT) functions to salvage adenine by converting it to adenosine-5-monophosphate (AMP). APRT deficiency in humans is a well characterized inborn error of metabolism, and APRT may contribute to the indispensable ... Full text Link to item Cite

Characterization of the SarA virulence gene regulator of Staphylococcus aureus.

Journal Article Mol Microbiol · July 1999 Staphylococcus aureus is a potent human pathogen that expresses a large number of virulence factors in a temporally regulated fashion. Two pleiotropically acting regulatory loci were identified in previous mutational studies. The agr locus comprises two op ... Full text Link to item Cite

Structural basis of multidrug recognition by BmrR, a transcription activator of a multidrug transporter.

Journal Article Cell · February 5, 1999 Multidrug-efflux transporters demonstrate an unusual ability to recognize multiple structurally dissimilar toxins. A comparable ability to bind diverse hydrophobic cationic drugs is characteristic of the Bacillus subtilis transcription regulator BmrR, whic ... Full text Link to item Cite

Escherichia coli purine repressor: key residues for the allosteric transition between active and inactive conformations and for interdomain signaling.

Journal Article Biochemistry · November 10, 1998 The Escherichia coli purine repressor, PurR, exists in an equilibrium between open and closed conformations. Binding of a corepressor, hypoxanthine or guanine, shifts the allosteric equilibrium in favor of the closed conformation and increases the operator ... Full text Link to item Cite

The human T-cell leukemia virus-1 transcriptional activator Tax enhances cAMP-responsive element-binding protein (CREB) binding activity through interactions with the DNA minor groove.

Journal Article J Biol Chem · July 24, 1998 Tax-1, the transcriptional activation protein of human T-cell leukemia virus-1, increases transcription from the human T-cell leukemia virus-1 long terminal repeat and specific cellular promoters through interactions with cellular DNA-binding proteins. The ... Full text Link to item Cite

Crystal structures of Toxoplasma gondii uracil phosphoribosyltransferase reveal the atomic basis of pyrimidine discrimination and prodrug binding.

Journal Article EMBO J · June 15, 1998 Uracil phosphoribosyltransferase (UPRTase) catalyzes the transfer of a ribosyl phosphate group from alpha-D-5-phosphoribosyl-1-pyrophosphate to the N1 nitrogen of uracil. The UPRTase from the opportunistic pathogen Toxoplasma gondii is a rational target fo ... Full text Link to item Cite

The structure of PurR mutant L54M shows an alternative route to DNA kinking.

Journal Article Nat Struct Biol · June 1998 The crystal structure of the purine repressor mutant L54M bound to hypoxanthine and to the purF operator provides a stereochemical understanding of the high DNA affinity of this hinge helix mutant. Comparison of the PurR L54M-DNA complex to that of the wil ... Full text Link to item Cite

Structure-based redesign of corepressor specificity of the Escherichia coli purine repressor by substitution of residue 190.

Journal Article Biochemistry · January 27, 1998 Guanine or hypoxanthine, physiological corepressors of the Escherichia coli purine repressor (PurR), promote formation of the ternary PurR-corepressor-operator DNA complex that functions to repress pur operon gene expression. Structure-based predictions on ... Full text Link to item Cite

Preliminary structural studies on the multi-ligand-binding domain of the transcription activator, BmrR, from Bacillus subtilis.

Journal Article Protein Sci · November 1997 In the bacterium Bacillus subtilis, the DNA-binding regulatory protein, BmrR, activates transcription from the multidrug transporter gene, bmr, after binding either rhodamine or tetraphenylphosphonium. These two compounds, which have no structural similari ... Full text Link to item Cite

The X-ray structure of the PurR-guanine-purF operator complex reveals the contributions of complementary electrostatic surfaces and a water-mediated hydrogen bond to corepressor specificity and binding affinity.

Journal Article J Biol Chem · September 5, 1997 The purine repressor, PurR, is the master regulatory protein of de novo purine nucleotide biosynthesis in Escherichia coli. This dimeric transcription factor is activated to bind to cognate DNA operator sites by initially binding either of its physiologica ... Full text Link to item Cite

Allosteric intermediates indicate R2 is the liganded hemoglobin end state.

Journal Article Proc Natl Acad Sci U S A · July 22, 1997 Hemoglobin has been a long-standing paradigm for understanding protein allostery. Here, the x-ray structures of two chemically crosslinked, fully liganded hemoglobins, alpha2beta82CA82beta and alpha2beta82ND82beta, are described at 2.3 A and 2.6 A resoluti ... Full text Link to item Cite

A positively charged residue bound in the minor groove does not alter the bending of a DNA duplex

Journal Article Journal of the American Chemical Society · December 25, 1996 Full text Cite

Crystal structures of Toxoplasma gondii HGXPRTase reveal the catalytic role of a long flexible loop.

Journal Article Nat Struct Biol · October 1996 Crystal structures of substrate-free and XMP-soaked hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase) of the opportunistic pathogen Toxoplasma gondii have been determined to 2.4 and 2.9 A resolution, respectively. HGXPRTase displays the c ... Full text Link to item Cite

Crystallization of the purine salvage enzyme adenine phosphoribosyltransferase.

Journal Article Proteins · August 1996 Adenine phosphoribosyltransferase from the protozoan parasite Leishmania donovani has been crystallized in the presence of the substrate Mg(2+)-alpha-D-5-phosphoribosyl-1-pyrophosphate (PRPP) or the product adenosine-5-monophosphate, as well as in the abse ... Full text Link to item Cite

Crystallization of the purine salvage enzyme adenine phosphoribosyltransferase

Journal Article Proteins: Structure, Function, and Genetics · August 1996 Full text Cite

Analysis of the structural properties of cAMP-responsive element-binding protein (CREB) and phosphorylated CREB.

Journal Article J Biol Chem · June 7, 1996 The transcription factor CREB (cAMP responsive element binding protein) is activated by protein kinase A (PKA) phosphorylation of a single serine residue. To investigate possible mechanisms of CREB regulation by phosphorylation, we initiated a structural a ... Full text Link to item Cite

Crystal structure of the lactose operon repressor and its complexes with DNA and inducer.

Journal Article Science · March 1, 1996 The lac operon of Escherichia coli is the paradigm for gene regulation. Its key component is the lac repressor, a product of the lacI gene. The three-dimensional structures of the intact lac repressor, the lac repressor bound to the gratuitous inducer isop ... Full text Link to item Cite

Structural comparison of the free and DNA-bound forms of the purine repressor DNA-binding domain.

Journal Article Structure · November 15, 1995 BACKGROUND: The purine repressor (PurR) regulates genes that encode enzymes for purine biosynthesis. PurR has a two domain structure with an N-terminal DNA-binding domain (DBD) and a C-terminal corepressor-binding domain (CBD). The three dimensional struct ... Full text Link to item Cite

Mechanism of corepressor-mediated specific DNA binding by the purine repressor.

Journal Article Cell · October 6, 1995 The modulation of the affinity of DNA-binding proteins by small molecule effectors for cognate DNA sites is common to both prokaryotes and eukaryotes. However, the mechanisms by which effector binding to one domain affects DNA binding by a distal domain ar ... Full text Link to item Cite

Allosteric transition intermediates modelled by crosslinked haemoglobins.

Journal Article Nature · May 4, 1995 The structural end-points of haemoglobin's transition from its low-oxygen-affinity (T) to high-oxygen-affinity (R) state, have been well established by X-ray crystallography, but short-lived intermediates have proved less amenable to X-ray studies. Here we ... Full text Link to item Cite

Conformational changes of purine repressor DNA-binding domain upon complexation with DNA.

Journal Article Nucleic Acids Symp Ser · 1995 The purine repressor (PurR) consists of two functional domains: an N-terminal DNA-binding domain and a C-terminal corepressor-binding domain. Recently, the structure of PurR-corepressor-operator ternary complex was determined by X-ray crystallography. In t ... Link to item Cite

Mutational analysis of the autoinhibitory domain of calmodulin kinase II.

Journal Article J Biol Chem · November 18, 1994 Calmodulin (CaM)-kinase II is inactive in the absence of Ca2+/CaM due to interaction of its autoinhibitory domain with its catalytic domain. Previous studies using synthetic autoinhibitory domain peptides (residues 281-302) identified several residues as i ... Link to item Cite

Modulatory function of CREB.CREM alpha heterodimers depends upon CREM alpha phosphorylation.

Journal Article J Biol Chem · November 18, 1994 The cAMP-responsive element (CRE) modulator protein CREM alpha has been proposed to be a negative regulator of the CRE-binding protein (CREB). Precisely how CREM alpha inhibits CREB function is unclear, however. CREM alpha and CREB have highly related stru ... Link to item Cite

Crystal structure of LacI member, PurR, bound to DNA: minor groove binding by alpha helices.

Journal Article Science · November 4, 1994 The three-dimensional structure of a ternary complex of the purine repressor, PurR, bound to both its corepressor, hypoxanthine, and the 16-base pair purF operator site has been solved at 2.7 A resolution by x-ray crystallography. The bipartite structure o ... Full text Link to item Cite

Crystallization and preliminary X-ray analysis of an Escherichia coli purine repressor-hypoxanthine-DNA complex.

Journal Article J Mol Biol · September 23, 1994 The purine repressor (PurR) is a DNA-binding protein, which together with a purine corepressor serves to regulate de novo purine and pyrimidine biosynthesis in Escherichia coli. PurR belongs to the structurally homologous lac repressor family of transcript ... Full text Link to item Cite

Nuclear protein CBP is a coactivator for the transcription factor CREB.

Journal Article Nature · July 21, 1994 The transcription factor CREB binds to a DNA element known as the cAMP-regulated enhancer (CRE). CREB is activated through phosphorylation by protein kinase A (PKA), but precisely how phosphorylation stimulates CREB function is unknown. One model is that p ... Full text Link to item Cite

Engineered leucine zippers show that hemiphosphorylated CREB complexes are transcriptionally active.

Journal Article Proc Natl Acad Sci U S A · October 1, 1993 The ability of basic/leucine zipper transcription factors to form homo- and heterodimers potentially increases the diversity of signaling pathways that can impinge upon a single genetic element. The capacity of these proteins to dimerize in various combina ... Full text Link to item Cite

Structural analysis of the purine repressor, an Escherichia coli DNA-binding protein.

Journal Article J Biol Chem · June 15, 1993 The purine repressor protein, PurR, is a member of the lac repressor, LacI, family of Escherichia coli DNA-binding proteins that bind DNA via a highly conserved N-terminal helix-turn-helix motif. Additionally, the members of this family display strong sequ ... Link to item Cite

Secondary structure creates mismatched base pairs required for high-affinity binding of cAMP response element-binding protein to the human enkephalin enhancer.

Journal Article Proc Natl Acad Sci U S A · May 15, 1993 Transactivation studies of the enkephalin enhancer indicate that two cAMP response elements (CRE-1 and CRE-2) are needed to mediate the transcriptional response to cAMP and to the CRE-binding protein (CREB) transcription factor. CRE-1 and CRE-2 are contain ... Full text Link to item Cite

Escherichia coli biotin holoenzyme synthetase/bio repressor crystal structure delineates the biotin- and DNA-binding domains.

Journal Article Proc Natl Acad Sci U S A · October 1, 1992 The three-dimensional structure of BirA, the repressor of the Escherichia coli biotin biosynthetic operon, has been determined by x-ray crystallography and refined to a crystallographic residual of 19.0% at 2.3-A resolution. BirA is a sequence-specific DNA ... Full text Link to item Cite

Crystallization and preliminary X-ray studies on the co-repressor binding domain of the Escherichia coli purine repressor.

Journal Article J Mol Biol · June 20, 1992 The purine repressor is a putative helix-turn-helix DNA-binding protein that regulates several genetic loci important in purine and pyrimidine metabolism in Escherichia coli. The protein is composed of two domains, an N-terminal DNA-binding domain and a C- ... Full text Link to item Cite

DNA recognition by the helix-turn-helix motif. Current Opinion in Structural Biology 1992, 2: 100...-108

Journal Article Current Opinion in Structural Biology · January 1, 1992 Highlights of the past year's studies on helix-turn-helix proteins include the striking details of DNA bending by Escherichia coli catabolite gene activator protein, the structure determination of the E. coli factor for inversion stimulation, and the conti ... Full text Cite

Interaction of the regulatory subunit (RII) of cAMP-dependent protein kinase with RII-anchoring proteins occurs through an amphipathic helix binding motif.

Journal Article J Biol Chem · August 5, 1991 The type II cAMP-dependent protein kinase is localized to specific subcellular environments through the binding of the regulatory subunit (RII) dimer to RII-anchoring proteins. Computer-aided analysis of secondary structure, performed on four RII-anchoring ... Link to item Cite

Structure of gamma-chymotrypsin in the range pH 2.0 to pH 10.5 suggests that gamma-chymotrypsin is a covalent acyl-enzyme adduct at low pH.

Journal Article Int J Biol Macromol · April 1991 Crystals of gamma-chymotrypsin (gamma-CHT) grown at pH 7.0 are stable from pH 2.0 to 11.0. Crystalline gamma-CHT therefore provides an unusually favourable system to observe the structure of a protein and its bound solvent over a broad range of pH. In this ... Full text Link to item Cite

Interactions of the helix-turn-helix binding domain. Current opinion in structural biology 1991, 1:80-88

Journal Article Current Opinion in Structural Biology · January 1, 1991 Recent studies of members of the helix-turn-helix class of DNA-binding proteins have indicated the importance of non-specific protein-phosphate 'positioning contacts' and revealed several novel features of protein-DNA recognition and binding. These novel f ... Full text Cite

Interactions of the helix-turn-helix binding domain

Journal Article Current Opinion in Structural Biology · 1991 Recent studies of members of the helix-turn-helix class of DNA-binding proteins have indicated the importance of non-specific protein-phosphate 'positioning contacts' and revealed several novel features of protein-DNA recognition and binding. These novel f ... Cite

Protein-DNA conformational changes in the crystal structure of a lambda Cro-operator complex.

Journal Article Proc Natl Acad Sci U S A · October 1990 The structure of a complex of bacteriophage lambda Cro protein with a 17-base-pair operator has been determined at 3.9-A resolution. Isomorphous derivatives obtained by the synthesis of site-specific iodinated DNA oligomers were of critical importance in s ... Full text Link to item Cite

Structural basis of DNA-protein recognition.

Journal Article Trends Biochem Sci · July 1989 Recent structure determinations of several repressor-operator complexes have shown how proteins can recognize specific binding sites on DNA. Although each of these repressor proteins belongs to the 'helix-turn-helix' class of DNA-binding proteins, they do ... Full text Link to item Cite

The helix-turn-helix DNA binding motif.

Journal Article J Biol Chem · February 5, 1989 Link to item Cite

Crystallization of the bifunctional biotin operon repressor.

Journal Article J Biol Chem · January 5, 1989 The bifunctional birA gene product, BirA, which represses the biotin biosynthetic bio operon and also activates biotin in Escherichia coli, has been crystallized. The crystals have the tetragonal space group P4(1)2(1)2, or its enantiomorph, with unit cell ... Link to item Cite

Crystallization of mutant lysozymes from bacteriophage T4

Journal Article Journal of Crystal Growth · July 2, 1988 The crystallization properties of a large number of T4 lysozyme mutant proteins have been analyzed. Approximately 80% of the mutant proteins crystallize under conditions very similar to those used for the wild-type protein, regardless of the type of amino ... Full text Cite

Studies on the crystallization of the cro protein-pseudo OR3 complex

Journal Article Journal of Crystal Growth · August 2, 1986 Crystals of a complex of cro protein and a 17 base-pair DNA operator fragment have been grown by vapor diffusion and controlled evaporation methods. The former method, although successful, was accompanied by crystal clustering, excessive nucleation, and a ... Full text Cite

Crystal structure of the promutagen O4-methylthymidine: importance of the anti conformation of the O(4) methoxy group and possible mispairing of O4-methylthymidine with guanine.

Journal Article Biochemistry · March 11, 1986 O4-Methylthymidine (O4medT) is a promutagen. To correlate its biological properties to changes in the electronic, geometric, and conformational properties of the pyrimidine base resulting from the keto to enol shift arising from methylation, an X-ray study ... Full text Link to item Cite

Crystallization of a complex of cro repressor with a 17 base-pair operator.

Journal Article J Mol Biol · March 5, 1986 Crystals of the lambda cro repressor complexed to a 17 base-pair synthetic binding site related to the OR3 operator have been obtained. The complex crystallizes in the hexagonal space group P6(2) (or P6(4)) with unit cell dimensions a = b = 154.8 A, c = 85 ... Full text Link to item Cite

Structure of a Z-DNA with two different backbone chain conformations. Stabilization of the decadeoxyoligonucleotide d(CGTACGTACG) by [Co(NH3)6]3+ binding to the guanine.

Journal Article J Biomol Struct Dyn · February 1986 The complex between cobalt hexammine and decadeoxyoligomer d(CGTACGTACG) crystallizes into the space group P65 with unit cell constants a = b = 17.93A, and c = 43.41A. The molecules have the helix axis coincident with the crystal c-axis. The decamers stack ... Full text Link to item Cite

Crystallization and preliminary crystallographic studies of the decadeoxyoligonucleotide d(CpGpTpApCpGpTpApCpG).

Journal Article J Mol Biol · February 20, 1985 Crystals of the self-complementary decadeoxyoligonucleotide d(CpGpTpApCpGpTpApCpG) have been grown from a solution containing [Co(NH3)6]Cl3 and spermine. The amber-colored crystals are hexagonal and belong to the space group P6(5) (or P6(1] with unit cell ... Full text Link to item Cite

X-ray structure of cytidine-5'-O-dimethylphosphate. Novel stacking between the ribosyl O(2') hydroxyl oxygen atom and the base.

Journal Article Nucleic Acids Res · September 11, 1984 The anionic oxygen atoms of the phosphodiester backbone of RNA and DNA are particularly susceptible to esterification by many mutagenic and carcinogenic alkylating agents. To better understand the geometric, electronic and conformational properties of the ... Full text Link to item Cite

Crystal Structure and Conformation of the Phosphotriester Adenosine 5’-O-(Diethyl phosphate). Possible Steric and Conformational Mechanisms for the Biochemical and Biological Effects Arising from Phosphate Alkylation

Journal Article Journal of the American Chemical Society · September 1, 1984 Phosphotriesterified oligonucleotides are often the major products resulting from the attack of mutagenic and carcinogenic alkylating agents on DNA and RNA. In order to elucidate the electronic and conformational perturbations arising from phosphate esteri ... Full text Cite

Crystal structure of O4-methyl uridine: stacking induced changes in the geometry of the pyrimidine ring and its mutagenic role.

Journal Article J Biomol Struct Dyn · December 1983 The geometric properties of the pyrimidine ring of O4-methyl uridine more closely resemble those of cytidine than diketo uridine. Differences between the independent molecules of O4-methyl uridine are observed in the C(7)-O(4)-C(4)-C(5)-C(6) bond orders an ... Full text Link to item Cite

Molecular and Crystal Structure of O4-Methyluridine. Reaction Coordinates for an Incipient Nucleophilic Attack Seen by Short Intermolecular Sugar-Base Interactions

Journal Article Journal of the American Chemical Society · December 1, 1983 Base-alkylated nucleosides are mutagenic in that they are capable of inducing base mispairing. Here we report the first structure of an O-alkylated pyrimidine nucleoside, O4-methyluridine (C10H14O6N2). ... Full text Cite

Left-handed DNA helices, supercoiling, and the B-Z junction.

Journal Article Cold Spring Harb Symp Quant Biol · 1983 Full text Link to item Cite

Occurrence of the unusual 2C5(1C4) chair conformation in two carbohydrates and the reverse anomeric effect. x-ray structures of 3, 4, 5, 7-tetra-o-acetyl-2, 6-anhydro-d-glycero-d-ido-heptonamide (1) AND 3, 4, 5, 7-tetra-o-acetyl-2, 6- anhydro-d-glyceroL-gluco-heptonamide (2)

Journal Article Journal of Carbohydrate Chemistry · January 1, 1982 The title compounds 1 and 2 (both C15O15NH21) crystallized in the monoclinic space group P21 (Z=2)owith a=8.864(1), b=8.346(1), c=13.569(1)A, β=114.12(1), V=918.1(2)A3, D(calc)=1.358 g/cc fo ... Full text Cite

Left-handed DNA helices, supercoiling, and the B-Z junction

Journal Article Cold Spring Harbor Symposia on Quantitative Biology · 1982 Cite

Androgen control of an inhibitory modulator of phosphodiesterase in rat epididymis and prostate.

Journal Article Endocrinology · April 1981 When rats were injected with the progestin ethynodiol diacetate in doses that suppressed spermatogenesis and the growth of accessory sex glands, the level of phosphodiesterase in epididymal and prostate tissues increased 5- to 10-fold. This increase was pr ... Full text Link to item Cite

Androgen control of phosphodiesterase modulator in epididymis and prostate of rat

Journal Article Federation Proceedings · January 1, 1980 Cite