Scholars@Duke
Pei Zhou

Pei Zhou

Professor of Biochemistry
Biochemistry
peizhou@biochem.duke.edu
Duke Box 3711, Durham, NC 27710
270 Sands Building, Research Drive, Durham, NC 27710
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Selected Publications

The landscape of small-molecule prodrugs.

Journal Article Nat Rev Drug Discov · May 2024 Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration to generate the API in situ. Although sharing this general characteristic, prodrugs enco ... Full text Link to item Cite

AI is a viable alternative to high throughput screening: a 318-target study.

Journal Article Sci Rep · April 2, 2024 High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can acce ... Full text Open Access Link to item Cite

DexDesign: an OSPREY-based algorithm for designing de novo D-peptide inhibitors.

Journal Article Protein Eng Des Sel · January 29, 2024 With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making ... Full text Open Access Link to item Cite

DexDesign: A New OSPREY-Based Algorithm for Designing de novo D-peptide Inhibitors

Conference Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) · January 1, 2024 D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. We introduce DexDesign, an OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors, and use it to design ... Full text Cite

Discovery, characterization, and redesign of potent antimicrobial thanatin orthologs from Chinavia ubica and Murgantia histrionica targeting E. coli LptA.

Journal Article J Struct Biol X · December 2023 Podisus maculiventris thanatin has been reported as a potent antimicrobial peptide with antibacterial and antifungal activity. Its antibiotic activity has been most thoroughly characterized against E. coli and shown to interfere with multiple pathways, suc ... Full text Link to item Cite

Bacterial pathogens deliver water- and solute-permeable channels to plant cells.

Journal Article Nature · September 2023 Many animal- and plant-pathogenic bacteria use a type III secretion system to deliver effector proteins into host cells1,2. Elucidation of how these effector proteins function in host cells is critical for understanding infectious diseases in animals and p ... Full text Open Access Link to item Cite

Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens.

Journal Article Sci Transl Med · August 9, 2023 The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting a ... Full text Link to item Cite

Seeing is believing: Understanding functions of NPR1 and its paralogs in plant immunity through cellular and structural analyses.

Journal Article Curr Opin Plant Biol · June 2023 In the past 30 years, our knowledge of how nonexpressor of pathogenesis-related genes 1 (NPR1) serves as a master regulator of salicylic acid (SA)-mediated immune responses in plants has been informed largely by molecular genetic studies. Despite extensive ... Full text Link to item Cite

Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH.

Journal Article ChemMedChem · June 1, 2023 Despite the widespread emergence of multidrug-resistant nosocomial Gram-negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram-negative pathogens has been approved over the past five decades. Theref ... Full text Link to item Cite

Structure and dynamics of the Arabidopsis O-fucosyltransferase SPINDLY.

Journal Article Nat Commun · March 20, 2023 SPINDLY (SPY) in Arabidopsis thaliana is a novel nucleocytoplasmic protein O-fucosyltransferase (POFUT), which regulates diverse developmental processes. Sequence analysis indicates that SPY is distinct from ER-localized POFUTs and contains N-terminal tetr ... Full text Open Access Link to item Cite

Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy.

Journal Article NAR Cancer · March 2023 DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The 'Y-family' trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate dam ... Full text Open Access Link to item Cite

Structural basis of NPR1 in activating plant immunity.

Journal Article Nature · May 2022 NPR1 is a master regulator of the defence transcriptome induced by the plant immune signal salicylic acid1-4. Despite the important role of NPR1 in plant immunity5-7, understanding of its regulatory mechanisms has been hindered by a lack of structural info ... Full text Link to item Cite

SARS-CoV-2 hijacks host cell genome instability pathways.

Journal Article Res Sq · April 14, 2022 The repertoire of coronavirus disease 2019 (COVID-19)-mediated adverse health outcomes has continued to expand in infected patients, including the susceptibility to developing long-COVID; however, the molecular underpinnings at the cellular level are poorl ... Full text Link to item Cite

MESH1 knockdown triggers proliferation arrest through TAZ repression.

Journal Article Cell Death Dis · March 10, 2022 All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main stress-coping mechanism is the stringent response triggered by the accumulation of "alarmone" (p)ppGpp to arrest proliferation a ... Full text Link to item Cite

The landscape of small-molecule prodrugs.

Journal Article Nat Rev Drug Discov · May 2024 Prodrugs are derivatives with superior properties compared with the parent active pharmaceutical ingredient (API), which undergo biotransformation after administration to generate the API in situ. Although sharing this general characteristic, prodrugs enco ... Full text Link to item Cite

AI is a viable alternative to high throughput screening: a 318-target study.

Journal Article Sci Rep · April 2, 2024 High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can acce ... Full text Open Access Link to item Cite

DexDesign: an OSPREY-based algorithm for designing de novo D-peptide inhibitors.

Journal Article Protein Eng Des Sel · January 29, 2024 With over 270 unique occurrences in the human genome, peptide-recognizing PDZ domains play a central role in modulating polarization, signaling, and trafficking pathways. Mutations in PDZ domains lead to diseases such as cancer and cystic fibrosis, making ... Full text Open Access Link to item Cite

DexDesign: A New OSPREY-Based Algorithm for Designing de novo D-peptide Inhibitors

Conference Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) · January 1, 2024 D-peptide inhibitors offer unique advantages as therapeutics, including increased metabolic stability and low immunogenicity. We introduce DexDesign, an OSPREY-based algorithm for computationally designing de novo D-peptide inhibitors, and use it to design ... Full text Cite

Discovery, characterization, and redesign of potent antimicrobial thanatin orthologs from Chinavia ubica and Murgantia histrionica targeting E. coli LptA.

Journal Article J Struct Biol X · December 2023 Podisus maculiventris thanatin has been reported as a potent antimicrobial peptide with antibacterial and antifungal activity. Its antibiotic activity has been most thoroughly characterized against E. coli and shown to interfere with multiple pathways, suc ... Full text Link to item Cite

Bacterial pathogens deliver water- and solute-permeable channels to plant cells.

Journal Article Nature · September 2023 Many animal- and plant-pathogenic bacteria use a type III secretion system to deliver effector proteins into host cells1,2. Elucidation of how these effector proteins function in host cells is critical for understanding infectious diseases in animals and p ... Full text Open Access Link to item Cite

Preclinical safety and efficacy characterization of an LpxC inhibitor against Gram-negative pathogens.

Journal Article Sci Transl Med · August 9, 2023 The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme in the biosynthesis of lipid A, the outer membrane anchor of lipopolysaccharide and lipooligosaccharide in Gram-negative bacteria. The development of LpxC-targeting a ... Full text Link to item Cite

Seeing is believing: Understanding functions of NPR1 and its paralogs in plant immunity through cellular and structural analyses.

Journal Article Curr Opin Plant Biol · June 2023 In the past 30 years, our knowledge of how nonexpressor of pathogenesis-related genes 1 (NPR1) serves as a master regulator of salicylic acid (SA)-mediated immune responses in plants has been informed largely by molecular genetic studies. Despite extensive ... Full text Link to item Cite

Development of LpxH Inhibitors Chelating the Active Site Dimanganese Metal Cluster of LpxH.

Journal Article ChemMedChem · June 1, 2023 Despite the widespread emergence of multidrug-resistant nosocomial Gram-negative bacterial infections and the major public health threat it brings, no new class of antibiotics for Gram-negative pathogens has been approved over the past five decades. Theref ... Full text Link to item Cite

Structure and dynamics of the Arabidopsis O-fucosyltransferase SPINDLY.

Journal Article Nat Commun · March 20, 2023 SPINDLY (SPY) in Arabidopsis thaliana is a novel nucleocytoplasmic protein O-fucosyltransferase (POFUT), which regulates diverse developmental processes. Sequence analysis indicates that SPY is distinct from ER-localized POFUTs and contains N-terminal tetr ... Full text Open Access Link to item Cite

Roles of trans-lesion synthesis (TLS) DNA polymerases in tumorigenesis and cancer therapy.

Journal Article NAR Cancer · March 2023 DNA damage tolerance and mutagenesis are hallmarks and enabling characteristics of neoplastic cells that drive tumorigenesis and allow cancer cells to resist therapy. The 'Y-family' trans-lesion synthesis (TLS) DNA polymerases enable cells to replicate dam ... Full text Open Access Link to item Cite

Structural basis of NPR1 in activating plant immunity.

Journal Article Nature · May 2022 NPR1 is a master regulator of the defence transcriptome induced by the plant immune signal salicylic acid1-4. Despite the important role of NPR1 in plant immunity5-7, understanding of its regulatory mechanisms has been hindered by a lack of structural info ... Full text Link to item Cite

SARS-CoV-2 hijacks host cell genome instability pathways.

Journal Article Res Sq · April 14, 2022 The repertoire of coronavirus disease 2019 (COVID-19)-mediated adverse health outcomes has continued to expand in infected patients, including the susceptibility to developing long-COVID; however, the molecular underpinnings at the cellular level are poorl ... Full text Link to item Cite

MESH1 knockdown triggers proliferation arrest through TAZ repression.

Journal Article Cell Death Dis · March 10, 2022 All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main stress-coping mechanism is the stringent response triggered by the accumulation of "alarmone" (p)ppGpp to arrest proliferation a ... Full text Link to item Cite

Adaptive Responses of Pseudomonas aeruginosa to Treatment with Antibiotics.

Journal Article Antimicrob Agents Chemother · January 18, 2022 Pseudomonas aeruginosa is among the highest priority pathogens for drug development because of its resistance to antibiotics, extraordinary adaptability, and persistence. Antipseudomonal research is strongly encouraged to address the acute scarcity of inno ... Full text Link to item Cite

Metazoan stringent-like response mediated by MESH1 phenotypic conservation via distinct mechanisms.

Journal Article Comput Struct Biotechnol J · 2022 All organisms are constantly exposed to various stresses, necessitating adaptive strategies for survival. In bacteria, the main metabolic stress-coping mechanism is the stringent response, which is triggered by the accumulation of "alarmone" (p)ppGpp to ar ... Full text Link to item Cite

SARS-CoV-2 triggers DNA damage response in Vero E6 cells.

Journal Article Biochem Biophys Res Commun · November 19, 2021 The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus responsible for the current COVID-19 pandemic and has now infected more than 200 million people with more than 4 million deaths globally. Recent data suggest that symptoms and gen ... Full text Link to item Cite

REV1 Inhibition Enhances Radioresistance and Autophagy.

Journal Article Cancers (Basel) · October 21, 2021 Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observations sug ... Full text Link to item Cite

Mutations in PBP2 from ceftriaxone-resistant Neisseria gonorrhoeae alter the dynamics of the β3-β4 loop to favor a low-affinity drug-binding state.

Journal Article J Biol Chem · October 2021 Resistance to the extended-spectrum cephalosporin ceftriaxone in the pathogenic bacteria Neisseria gonorrhoeae is conferred by mutations in penicillin-binding protein 2 (PBP2), the lethal target of the antibiotic, but how these mutations exert their effect ... Full text Link to item Cite

Direct photoresponsive inhibition of a p53-like transcription activation domain in PIF3 by Arabidopsis phytochrome B.

Journal Article Nat Commun · September 23, 2021 Photoactivated phytochrome B (PHYB) binds to antagonistically acting PHYTOCHROME-INTERACTING transcription FACTORs (PIFs) to regulate hundreds of light responsive genes in Arabidopsis by promoting PIF degradation. However, whether PHYB directly controls th ... Full text Link to item Cite

REV1 Inhibition Enhances Radioresistance and Autophagy

Journal Article · September 13, 2021 Cancer therapy resistance is a persistent clinical challenge. Recently, inhibition of the mutagenic translesion synthesis (TLS) protein REV1 was shown to enhance tumor cell response to chemotherapy by triggering senescence hallmarks. These observat ... Full text Cite

Oncogenic KRAS is dependent upon an EFR3A-PI4KA signaling axis for potent tumorigenic activity.

Journal Article Nat Commun · September 9, 2021 The HRAS, NRAS, and KRAS genes are collectively mutated in a fifth of all human cancers. These mutations render RAS GTP-bound and active, constitutively binding effector proteins to promote signaling conducive to tumorigenic growth. To further elucidate ho ... Full text Link to item Cite

The regulation of ferroptosis by MESH1 through the activation of the integrative stress response.

Journal Article Cell Death Dis · July 22, 2021 All organisms exposed to metabolic and environmental stresses have developed various stress adaptive strategies to maintain homeostasis. The main bacterial stress survival mechanism is the stringent response triggered by the accumulation "alarmone" (p)ppGp ... Full text Link to item Cite

Francisella FlmX broadly affects lipopolysaccharide modification and virulence.

Journal Article Cell Rep · June 15, 2021 The outer membrane protects Gram-negative bacteria from the host environment. Lipopolysaccharide (LPS), a major outer membrane constituent, has distinct components (lipid A, core, O-antigen) generated by specialized pathways. In this study, we describe the ... Full text Link to item Cite

Structure- and Ligand-Dynamics-Based Design of Novel Antibiotics Targeting Lipid A Enzymes LpxC and LpxH in Gram-Negative Bacteria.

Journal Article Acc Chem Res · April 6, 2021 Bacterial infections caused by multi-drug-resistant Gram-negative pathogens pose a serious threat to public health. Gram-negative bacteria are characterized by the enrichment of lipid A-anchored lipopolysaccharide (LPS) or lipooligosaccharide (LOS) in the ... Full text Link to item Cite

Degradation of Components of the Lpt Transenvelope Machinery Reveals LPS-Dependent Lpt Complex Stability in Escherichia coli.

Journal Article Front Mol Biosci · 2021 Lipopolysaccharide (LPS) is a peculiar component of the outer membrane (OM) of many Gram-negative bacteria that renders these bacteria highly impermeable to many toxic molecules, including antibiotics. LPS is assembled at the OM by a dedicated intermembran ... Full text Open Access Link to item Cite

REV1 inhibitor JH-RE-06 enhances tumor cell response to chemotherapy by triggering senescence hallmarks.

Journal Article Proc Natl Acad Sci U S A · November 17, 2020 REV1/POLζ-dependent mutagenic translesion synthesis (TLS) promotes cell survival after DNA damage but is responsible for most of the resulting mutations. A novel inhibitor of this pathway, JH-RE-06, promotes cisplatin efficacy in cancer cells and mouse xen ... Full text Link to item Cite

Rev7 loss alters cisplatin response and increases drug efficacy in chemotherapy-resistant lung cancer.

Journal Article Proc Natl Acad Sci U S A · November 17, 2020 Cisplatin is a standard of care for lung cancer, yet platinum therapy rarely results in substantial tumor regression or a dramatic extension in patient survival. Here, we examined whether targeting Rev7 (also referred to as Mad2B, Mad2L2, and FANCV), a com ... Full text Link to item Cite

Synthesis and evaluation of sulfonyl piperazine LpxH inhibitors.

Journal Article Bioorg Chem · September 2020 The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is essential in lipid A biosynthesis and has emerged as a promising target for the development of novel antibiotics against multidrug-resistant Gram-negative pathogens. Recently, we reported the cr ... Full text Link to item Cite

MESH1 is a cytosolic NADPH phosphatase that regulates ferroptosis.

Journal Article Nature metabolism · March 2020 Critical to the bacterial stringent response is the rapid relocation of resources from proliferation toward stress survival through the respective accumulation and degradation of (p)ppGpp by RelA and SpoT homologues. While mammalian genomes encode MESH1, a ... Full text Open Access Cite

Structural basis of the UDP-diacylglucosamine pyrophosphohydrolase LpxH inhibition by sulfonyl piperazine antibiotics.

Journal Article Proc Natl Acad Sci U S A · February 25, 2020 The UDP-2,3-diacylglucosamine pyrophosphate hydrolase LpxH is an essential lipid A biosynthetic enzyme that is conserved in the majority of gram-negative bacteria. It has emerged as an attractive novel antibiotic target due to the recent discovery of an Lp ... Full text Link to item Cite

Metabolic engineering of Escherichia coli to produce a monophosphoryl lipid A adjuvant.

Journal Article Metab Eng · January 2020 Monophosphoryl lipid A (MPLA) species, including MPL (a trade name of GlaxoSmithKline) and GLA (a trade name of Immune Design, a subsidiary of Merck), are widely used as an adjuvant in vaccines, allergy drugs, and immunotherapy to boost the immune response ... Full text Open Access Link to item Cite

A Small Molecule Targeting Mutagenic Translesion Synthesis Improves Chemotherapy.

Journal Article Cell · June 27, 2019 Intrinsic and acquired drug resistance and induction of secondary malignancies limit successful chemotherapy. Because mutagenic translesion synthesis (TLS) contributes to chemoresistance as well as treatment-induced mutations, targeting TLS is an attractiv ... Full text Link to item Cite

The Lipid A 1-Phosphatase, LpxE, Functionally Connects Multiple Layers of Bacterial Envelope Biogenesis.

Journal Article mBio · June 18, 2019 Although distinct lipid phosphatases are thought to be required for processing lipid A (component of the outer leaflet of the outer membrane), glycerophospholipid (component of the inner membrane and the inner leaflet of the outer membrane), and undecapren ... Full text Open Access Link to item Cite

NCP activates chloroplast transcription by controlling phytochrome-dependent dual nuclear and plastidial switches.

Journal Article Nat Commun · June 14, 2019 Phytochromes initiate chloroplast biogenesis by activating genes encoding the photosynthetic apparatus, including photosynthesis-associated plastid-encoded genes (PhAPGs). PhAPGs are transcribed by a bacterial-type RNA polymerase (PEP), but how phytochrome ... Full text Open Access Link to item Cite

Structure-Activity Relationship of Sulfonyl Piperazine LpxH Inhibitors Analyzed by an LpxE-Coupled Malachite Green Assay.

Journal Article ACS Infect Dis · April 12, 2019 The UDP-2,3-diacylglucosamine pyrophosphatase LpxH in the Raetz pathway of lipid A biosynthesis is an essential enzyme in the vast majority of Gram-negative pathogens and an excellent novel antibiotic target. The 32P-radioautographic thin-layer chromatogra ... Full text Link to item Cite

Antimicrobial Resistance in Neisseria gonorrhoeae: Proceedings of the STAR Sexually Transmitted Infection-Clinical Trial Group Programmatic Meeting.

Journal Article Sex Transm Dis · March 2019 The goal of the Sexually Transmitted Infection Clinical Trial Group's Antimicrobial Resistance (AMR) in Neisseria gonorrhoeae (NG) meeting was to assemble experts from academia, government, nonprofit and industry to discuss the current state of research, g ... Full text Link to item Cite

Lipid A Has Significance for Optimal Growth of Coxiella burnetii in Macrophage-Like THP-1 Cells and to a Lesser Extent in Axenic Media and Non-phagocytic Cells.

Journal Article Front Cell Infect Microbiol · 2018 Lipid A is an essential basal component of lipopolysaccharide of most Gram-negative bacteria. Inhibitors targeting LpxC, a conserved enzyme in lipid A biosynthesis, are antibiotic candidates against Gram-negative pathogens. Here we report the characterizat ... Full text Link to item Cite

A pH-gated conformational switch regulates the phosphatase activity of bifunctional HisKA-family histidine kinases.

Journal Article Nat Commun · December 13, 2017 Histidine kinases are key regulators in the bacterial two-component systems that mediate the cellular response to environmental changes. The vast majority of the sensor histidine kinases belong to the bifunctional HisKA family, displaying both kinase and p ... Full text Link to item Cite

Structure, inhibition, and regulation of essential lipid A enzymes.

Journal Article Biochim Biophys Acta Mol Cell Biol Lipids · November 2017 The Raetz pathway of lipid A biosynthesis plays a vital role in the survival and fitness of Gram-negative bacteria. Research efforts in the past three decades have identified individual enzymes of the pathway and have provided a mechanistic understanding o ... Full text Open Access Link to item Cite

Probing the excited-state chemical shifts and exchange parameters by nitrogen-decoupled amide proton chemical exchange saturation transfer (HNdec-CEST).

Journal Article Chem Commun (Camb) · July 27, 2017 CEST-NMR spectroscopy is a powerful tool for probing the conformational dynamics of macromolecules. We present a HNdec-CEST experiment that simplifies the relaxation matrix, reduces fitting parameters, and enhances signal resolution. Importantly, fitting o ... Full text Open Access Link to item Cite

Curative Treatment of Severe Gram-Negative Bacterial Infections by a New Class of Antibiotics Targeting LpxC.

Journal Article mBio · July 25, 2017 The infectious diseases caused by multidrug-resistant bacteria pose serious threats to humankind. It has been suggested that an antibiotic targeting LpxC of the lipid A biosynthetic pathway in Gram-negative bacteria is a promising strategy for curing Gram- ... Full text Open Access Link to item Cite

The Arabidopsis O-fucosyltransferase SPINDLY activates nuclear growth repressor DELLA.

Journal Article Nat Chem Biol · May 2017 Plant development requires coordination among complex signaling networks to enhance the plant's adaptation to changing environments. DELLAs, transcription regulators originally identified as repressors of phytohormone gibberellin signaling, play a central ... Full text Open Access Link to item Cite

Synthesis and biological evaluation of sulfonyl piperazine derivatives for LpxH inhibition

Conference ABSTRACTS OF PAPERS OF THE AMERICAN CHEMICAL SOCIETY · April 2, 2017 Link to item Cite

CLEAN

Chapter · January 1, 2017 CLEAN is an algorithm for the suppression of artifacts from nonuniform sampling, originally developed in the field of radioastronomy in the 1960s and 1970s. Recognizing similarities between the problem of NMR NUS and astronomical data collection, several N ... Full text Cite

Backprojection and Related Methods

Chapter · January 1, 2017 The sampling of the NMR time domain along radial spokes allows one to obtain projections of an NMR spectrum at various angles. These projections encode information about the positions, intensities, and lineshapes of the peaks in the spectrum, and this info ... Full text Cite

High susceptibility of MDR and XDR Gram-negative pathogens to biphenyl-diacetylene-based difluoromethyl-allo-threonyl-hydroxamate LpxC inhibitors.

Journal Article J Antimicrob Chemother · October 2016 OBJECTIVES: Inhibitors of uridine diphosphate-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC, which catalyses the first, irreversible step in lipid A biosynthesis) are a promising new class of antibiotics against Gram-negative bacteria. T ... Full text Open Access Link to item Cite

Structure of the essential Haemophilus influenzae UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis.

Journal Article Nat Microbiol · August 15, 2016 In most Gram-negative pathogens, the hydrolysis of UDP-2,3-diacylglucosamine to generate lipid X in lipid A biosynthesis is catalysed by the membrane-associated enzyme LpxH. We report the crystal structure of LpxH in complex with its product, lipid X, unve ... Full text Open Access Link to item Cite

Unbiased measurements of reconstruction fidelity of sparsely sampled magnetic resonance spectra.

Journal Article Nat Commun · July 27, 2016 The application of sparse-sampling techniques to NMR data acquisition would benefit from reliable quality measurements for reconstructed spectra. We introduce a pair of noise-normalized measurements, and , for differentiating inadequate modelling from over ... Full text Open Access Link to item Cite

A Scalable Synthesis of the Difluoromethyl-allo-threonyl Hydroxamate-Based LpxC Inhibitor LPC-058.

Journal Article J Org Chem · May 20, 2016 The difluoromethyl-allo-threonyl hydroxamate-based compound LPC-058 is a potent inhibitor of UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase (LpxC) in Gram-negative bacteria. A scalable synthesis of this compound is described. The key step i ... Full text Open Access Link to item Cite

Discovery of the Elusive UDP-Diacylglucosamine Hydrolase in the Lipid A Biosynthetic Pathway in Chlamydia trachomatis.

Journal Article mBio · March 22, 2016 Constitutive biosynthesis of lipid A via the Raetz pathway is essential for the viability and fitness of Gram-negative bacteria, includingChlamydia trachomatis Although nearly all of the enzymes in the lipid A biosynthetic pathway are highly conserved acro ... Full text Open Access Link to item Cite

Drug design from the cryptic inhibitor envelope.

Journal Article Nat Commun · February 25, 2016 Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here w ... Full text Open Access Link to item Cite

Suppression of conformational heterogeneity at a protein-protein interface.

Journal Article Proc Natl Acad Sci U S A · July 21, 2015 Staphylococcal protein A (SpA) is an important virulence factor from Staphylococcus aureus responsible for the bacterium's evasion of the host immune system. SpA includes five small three-helix-bundle domains that can each bind with high affinity to many h ... Full text Open Access Link to item Cite

Systematic solution to homo-oligomeric structures determined by NMR.

Journal Article Proteins · April 2015 Protein structure determination by NMR has predominantly relied on simulated annealing-based conformational search for a converged fold using primarily distance constraints, including constraints derived from nuclear Overhauser effects, paramagnetic relaxa ... Full text Link to item Cite

Ubiquitin recognition by FAAP20 expands the complex interface beyond the canonical UBZ domain.

Journal Article Nucleic Acids Res · December 16, 2014 FAAP20 is an integral component of the Fanconi anemia core complex that mediates the repair of DNA interstrand crosslinks. The ubiquitin-binding capacity of the FAAP20 UBZ is required for recruitment of the Fanconi anemia complex to interstrand DNA crossli ... Full text Open Access Link to item Cite

Structural basis of lipid binding for the membrane-embedded tetraacyldisaccharide-1-phosphate 4'-kinase LpxK.

Journal Article J Biol Chem · August 29, 2014 The membrane-bound tetraacyldisaccharide-1-phosphate 4'-kinase, LpxK, catalyzes the sixth step of the lipid A (Raetz) biosynthetic pathway and is a viable antibiotic target against emerging Gram-negative pathogens. We report the crystal structure of lipid ... Full text Link to item Cite

A CRISPR-Cas system enhances envelope integrity mediating antibiotic resistance and inflammasome evasion.

Journal Article Proc Natl Acad Sci U S A · July 29, 2014 Clustered, regularly interspaced, short palindromic repeats-CRISPR associated (CRISPR-Cas) systems defend bacteria against foreign nucleic acids, such as during bacteriophage infection and transformation, processes which cause envelope stress. It is unclea ... Full text Link to item Cite

Sparsely-sampled, high-resolution 4-D omit spectra for detection and assignment of intermolecular NOEs of protein complexes.

Journal Article J Biomol NMR · June 2014 Unambiguous detection and assignment of intermolecular NOEs are essential for structure determination of protein complexes by NMR. Such information has traditionally been obtained with 3-D half-filtered experiments, where scalar coupling-based purging of i ... Full text Link to item Cite

Structural basis of the promiscuous inhibitor susceptibility of Escherichia coli LpxC.

Journal Article ACS Chem Biol · January 17, 2014 The LpxC enzyme in the lipid A biosynthetic pathway is one of the most promising and clinically unexploited antibiotic targets for treatment of multidrug-resistant Gram-negative infections. Progress in medicinal chemistry has led to the discovery of potent ... Full text Link to item Cite

Chasing acyl carrier protein through a catalytic cycle of lipid A production.

Journal Article Nature · January 16, 2014 Acyl carrier protein represents one of the most highly conserved proteins across all domains of life and is nature's way of transporting hydrocarbon chains in vivo. Notably, type II acyl carrier proteins serve as a crucial interaction hub in primary cellul ... Full text Link to item Cite

Chasing acyl carrier protein through a catalytic cycle of lipid A production

Journal Article Nature · January 1, 2014 Acyl carrier protein represents one of the most highly conserved proteins across all domains of life and is nature's way of transporting hydrocarbon chains in vivo. Notably, type II acyl carrier proteins serve as a crucial interaction hub in primary cellul ... Full text Cite

The UDP-diacylglucosamine pyrophosphohydrolase LpxH in lipid A biosynthesis utilizes Mn2+ cluster for catalysis.

Journal Article J Biol Chem · September 20, 2013 In Escherichia coli and the majority of β- and γ-proteobacteria, the fourth step of lipid A biosynthesis, i.e. cleavage of the pyrophosphate group of UDP-2,3-diacyl-GlcN, is carried out by LpxH. LpxH has been previously suggested to contain signature motif ... Full text Link to item Cite

Synthesis, structure, and antibiotic activity of aryl-substituted LpxC inhibitors.

Journal Article J Med Chem · September 12, 2013 The zinc-dependent deacetylase LpxC catalyzes the committed step of lipid A biosynthesis in Gram-negative bacteria and is a validated target for the development of novel antibiotics to combat multidrug-resistant Gram-negative infections. Many potent LpxC i ... Full text Link to item Cite

Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis.

Journal Article Science · August 30, 2013 MraY (phospho-MurNAc-pentapeptide translocase) is an integral membrane enzyme that catalyzes an essential step of bacterial cell wall biosynthesis: the transfer of the peptidoglycan precursor phospho-MurNAc-pentapeptide to the lipid carrier undecaprenyl ph ... Full text Link to item Cite

Storage of hydrogen spin polarization in long-lived 13C2 singlet order and implications for hyperpolarized magnetic resonance imaging.

Journal Article J Am Chem Soc · July 3, 2013 Hyperpolarized magnetic resonance imaging (MRI) is a powerful technique enabling real-time monitoring of metabolites at concentration levels not accessible by standard MRI techniques. A considerable challenge this technique faces is the T1 decay of the hyp ... Full text Link to item Cite

Specific interaction of the transcription elongation regulator TCERG1 with RNA polymerase II requires simultaneous phosphorylation at Ser2, Ser5, and Ser7 within the carboxyl-terminal domain repeat.

Journal Article J Biol Chem · April 12, 2013 The human transcription elongation regulator TCERG1 physically couples transcription elongation and splicing events by interacting with splicing factors through its N-terminal WW domains and the hyperphosphorylated C-terminal domain (CTD) of RNA polymerase ... Full text Link to item Cite

Extracting structural information from residual chemical shift anisotropy: Analytic solutions for peptide plane orientations and applications to determine protein structure

Journal Article Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) · April 3, 2013 Residual dipolar coupling (RDC) and residual chemical shift anisotropy (RCSA) provide orientational restraints on internuclear vectors and the principal axes of chemical shift anisotropy (CSA) tensors, respectively. Mathematically, while an RDC represents ... Full text Cite

Mechanistic characterization of the tetraacyldisaccharide-1-phosphate 4'-kinase LpxK involved in lipid A biosynthesis.

Journal Article Biochemistry · April 2, 2013 The sixth step in the lipid A biosynthetic pathway involves phosphorylation of the tetraacyldisaccharide-1-phosphate (DSMP) intermediate by the cytosol-facing inner membrane kinase LpxK, a member of the P-loop-containing nucleoside triphosphate (NTP) hydro ... Full text Link to item Cite

Mutants resistant to LpxC inhibitors by rebalancing cellular homeostasis.

Journal Article J Biol Chem · February 22, 2013 LpxC, the deacetylase that catalyzes the second and committed step of lipid A biosynthesis in Escherichia coli, is an essential enzyme in virtually all gram-negative bacteria and is one of the most promising antibiotic targets for treatment of multidrug-re ... Full text Link to item Cite

HASH: a program to accurately predict protein Hα shifts from neighboring backbone shifts.

Journal Article J Biomol NMR · January 2013 Chemical shifts provide not only peak identities for analyzing nuclear magnetic resonance (NMR) data, but also an important source of conformational information for studying protein structures. Current structural studies requiring H(α) chemical shifts suff ... Full text Link to item Cite

Crystal structure of MraY, an essential membrane enzyme for bacterial cell wall synthesis

Journal Article Science · 2013 MraY (phospho-MurNAc-pentapeptide translocase) is an integral membrane enzyme that catalyzes an essential step of bacterial cell wall biosynthesis: the transfer of the peptidoglycan precursor phospho-MurNAc-pentapeptide to the lipid carrier undecaprenyl ph ... Full text Cite

Rapid protein global fold determination using ultrasparse sampling, high-dynamic range artifact suppression, and time-shared NOESY.

Journal Article J Am Chem Soc · November 14, 2012 In structural studies of large proteins by NMR, global fold determination plays an increasingly important role in providing a first look at a target's topology and reducing assignment ambiguity in NOESY spectra of fully protonated samples. In this work, we ... Full text Link to item Cite

Structural basis of Rev1-mediated assembly of a quaternary vertebrate translesion polymerase complex consisting of Rev1, heterodimeric polymerase (Pol) ζ, and Pol κ.

Journal Article J Biol Chem · September 28, 2012 DNA synthesis across lesions during genomic replication requires concerted actions of specialized DNA polymerases in a potentially mutagenic process known as translesion synthesis. Current models suggest that translesion synthesis in mammalian cells is ach ... Full text Link to item Cite

Multifaceted recognition of vertebrate Rev1 by translesion polymerases ζ and κ.

Journal Article J Biol Chem · July 27, 2012 Translesion synthesis is a fundamental biological process that enables DNA replication across lesion sites to ensure timely duplication of genetic information at the cost of replication fidelity, and it is implicated in development of cancer drug resistanc ... Full text Link to item Cite

Efficient acquisition of high-resolution 4-D diagonal-suppressed methyl-methyl NOESY for large proteins.

Journal Article J Magn Reson · May 2012 The methyl-methyl NOESY experiment plays an important role in determining the global folds of large proteins. Despite the high sensitivity of this experiment, the analysis of methyl-methyl NOEs is frequently hindered by the limited chemical shift dispersio ... Full text Link to item Cite

¹H, ¹³C and ¹⁵N backbone and side-chain resonance assignments of Drosophila melanogaster Ssu72.

Journal Article Biomol NMR Assign · April 2012 Ssu72 helps regulate transcription and co-transcriptional mRNA processing by dephosphorylating serine residues at the 5th position in the heptad repeats of the C-terminal domain of RNA polymerase II. Here we use multidimensional, multinuclear NMR experimen ... Full text Link to item Cite

Protein loop closure using orientational restraints from NMR data.

Journal Article Proteins · February 2012 Protein loops often play important roles in biological functions. Modeling loops accurately is crucial to determining the functional specificity of a protein. Despite the recent progress in loop prediction approaches, which led to a number of algorithms ov ... Full text Link to item Cite

ADAM9 inhibition increases membrane activity of ADAM10 and controls α-secretase processing of amyloid precursor protein.

Journal Article J Biol Chem · November 25, 2011 Prodomains of A disintegrin and metalloproteinase (ADAM) metallopeptidases can act as highly specific intra- and intermolecular inhibitors of ADAM catalytic activity. The mouse ADAM9 prodomain (proA9; amino acids 24-204), expressed and characterized from E ... Full text Link to item Cite

A Bayesian approach for determining protein side-chain rotamer conformations using unassigned NOE data.

Journal Article J Comput Biol · November 2011 A major bottleneck in protein structure determination via nuclear magnetic resonance (NMR) is the lengthy and laborious process of assigning resonances and nuclear Overhauser effect (NOE) cross peaks. Recent studies have shown that accurate backbone folds ... Full text Link to item Cite

A geometric arrangement algorithm for structure determination of symmetric protein homo-oligomers from NOEs and RDCs.

Journal Article J Comput Biol · November 2011 Nuclear magnetic resonance (NMR) spectroscopy is a primary tool to perform structural studies of proteins in physiologically-relevant solution conditions. Restraints on distances between pairs of nuclei in the protein, derived from the nuclear Overhauser e ... Full text Link to item Cite

Protein side-chain resonance assignment and NOE assignment using RDC-defined backbones without TOCSY data.

Journal Article J Biomol NMR · August 2011 One bottleneck in NMR structure determination lies in the laborious and time-consuming process of side-chain resonance and NOE assignments. Compared to the well-studied backbone resonance assignment problem, automated side-chain resonance and NOE assignmen ... Full text Link to item Cite

Lipooligosaccharide is required for the generation of infectious elementary bodies in Chlamydia trachomatis.

Journal Article Proc Natl Acad Sci U S A · June 21, 2011 Lipopolysaccharides (LPS) and lipooligosaccharides (LOS) are the main lipid components of bacterial outer membranes and are essential for cell viability in most Gram-negative bacteria. Here we show that small molecule inhibitors of LpxC [UDP-3-O-(R-3-hydro ... Full text Link to item Cite

A graphical method for analyzing distance restraints using residual dipolar couplings for structure determination of symmetric protein homo-oligomers.

Journal Article Protein Sci · June 2011 High-resolution structure determination of homo-oligomeric protein complexes remains a daunting task for NMR spectroscopists. Although isotope-filtered experiments allow separation of intermolecular NOEs from intramolecular NOEs and determination of the st ... Full text Link to item Cite

Sparsely sampled high-resolution 4-D experiments for efficient backbone resonance assignment of disordered proteins.

Journal Article J Magn Reson · March 2011 Intrinsically disordered proteins (IDPs) play important roles in many critical cellular processes. Due to their limited chemical shift dispersion, IDPs often require four pairs of resonance connectivities (H(α), C(α), C(β) and CO) for establishing sequenti ... Full text Link to item Cite

cis-Proline-mediated Ser(P)5 dephosphorylation by the RNA polymerase II C-terminal domain phosphatase Ssu72.

Journal Article J Biol Chem · February 18, 2011 RNA polymerase II coordinates co-transcriptional events by recruiting distinct sets of nuclear factors to specific stages of transcription via changes of phosphorylation patterns along its C-terminal domain (CTD). Although it has become increasingly clear ... Full text Link to item Cite

Species-specific and inhibitor-dependent conformations of LpxC: implications for antibiotic design.

Journal Article Chem Biol · January 28, 2011 LpxC is an essential enzyme in the lipid A biosynthetic pathway in gram-negative bacteria. Several promising antimicrobial lead compounds targeting LpxC have been reported, though they typically display a large variation in potency against different gram-n ... Full text Link to item Cite

Syntheses, structures and antibiotic activities of LpxC inhibitors based on the diacetylene scaffold.

Journal Article Bioorg Med Chem · January 15, 2011 Compounds inhibiting LpxC in the lipid A biosynthetic pathway are promising leads for novel antibiotics against multidrug-resistant Gram-negative pathogens. We report the syntheses and structural and biochemical characterizations of LpxC inhibitors based o ... Full text Link to item Cite

A Bayesian Approach for Determining Protein Side-Chain Rotamer Conformations Using Unassigned NOE Data

Journal Article Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) · January 1, 2011 A major bottleneck in protein structure determination via nuclear magnetic resonance (NMR) is the lengthy and laborious process of assigning resonances and nuclear Overhauser effect (NOE) cross peaks. Recent studies have shown that accurate backbone folds ... Full text Cite

Protein Loop Closure Using Orientational Restraints from NMR Data

Journal Article Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) · January 1, 2011 Protein loops often play important roles in biological functions such as binding, recognition, catalytic activities and allosteric regulation. Modeling loops that are biophysically sensible is crucial to determining the functional specificity of a protein. ... Full text Cite

A Geometric Arrangement Algorithm for Structure Determination of Symmetric Protein Homo-oligomers from NOEs and RDCs

Journal Article Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) · January 1, 2011 Nuclear magnetic resonance (NMR) spectroscopy is a primary tool to perform structural studies of proteins in the physiologically-relevant solution-state. Restraints on distances between pairs of nuclei in the protein, derived from the nuclear Overhauser ef ... Full text Cite

A Markov random field framework for protein side-chain resonance assignment

Journal Article Lecture Notes in Computer Science (including subseries Lecture Notes in Artificial Intelligence and Lecture Notes in Bioinformatics) · December 23, 2010 Nuclear magnetic resonance (NMR) spectroscopy plays a critical role in structural genomics, and serves as a primary tool for determining protein structures, dynamics and interactions in physiologically-relevant solution conditions. The current speed of pro ... Full text Cite

HDAC6 and Ubp-M BUZ domains recognize specific C-terminal sequences of proteins.

Journal Article Biochemistry · December 21, 2010 The BUZ/Znf-UBP domain is a protein module found in the cytoplasmic deacetylase HDAC6, E3 ubiquitin ligase BRAP2/IMP, and a subfamily of ubiquitin-specific proteases. Although several BUZ domains have been shown to bind ubiquitin with high affinity by reco ... Full text Open Access Link to item Cite

Algorithms and analytic solutions using sparse residual dipolar couplings for high-resolution automated protein backbone structure determination by NMR

Journal Article Springer Tracts in Advanced Robotics · December 20, 2010 Developing robust and automated protein structure determination algorithms using nuclear magnetic resonance (NMR) data is an important goal in computational structural biology. Algorithms based on global orientational restraints from residual dipolar coupl ... Full text Cite

The unusual UBZ domain of Saccharomyces cerevisiae polymerase η.

Journal Article DNA Repair (Amst) · November 10, 2010 Recent research has revealed the presence of ubiquitin-binding domains in the Y family polymerases. The ubiquitin-binding zinc finger (UBZ) domain of human polymerase η is vital for its regulation, localization, and function. Here, we elucidate structural ... Full text Link to item Cite

Radial sampling for fast NMR: Concepts and practices over three decades.

Journal Article Prog Nucl Magn Reson Spectrosc · November 2010 Full text Link to item Cite

Fast acquisition of high resolution 4-D amide-amide NOESY with diagonal suppression, sparse sampling and FFT-CLEAN.

Journal Article J Magn Reson · May 2010 Amide-amide NOESY provides important distance constraints for calculating global folds of large proteins, especially integral membrane proteins with beta-barrel folds. Here, we describe a diagonal-suppressed 4-D NH-NH TROSY-NOESY-TROSY (ds-TNT) experiment ... Full text Link to item Cite

Assignment of 1H, 13C and 15N backbone resonances of Escherichia coli LpxC bound to L-161,240.

Journal Article Biomol NMR Assign · April 2010 The UDP-3-O-(R-3-hydroxymyristoyl)-N-acetylglucosamine deacetylase LpxC catalyzes the committed reaction of lipid A biosynthesis, an essential pathway in Gram-negative bacteria. We report the backbone resonance assignments of the 34 kDa LpxC from Escherich ... Full text Link to item Cite

Unconventional ubiquitin recognition by the ubiquitin-binding motif within the Y family DNA polymerases iota and Rev1.

Journal Article Mol Cell · February 12, 2010 Translesion synthesis is an essential cell survival strategy to promote replication after DNA damage. The accumulation of Y family polymerases (pol) iota and Rev1 at the stalled replication machinery is mediated by the ubiquitin-binding motifs (UBMs) of th ... Full text Link to item Cite

Overcoming the solubility limit with solubility-enhancement tags: successful applications in biomolecular NMR studies.

Journal Article J Biomol NMR · January 2010 Although the rapid progress of NMR technology has significantly expanded the range of NMR-trackable systems, preparation of NMR-suitable samples that are highly soluble and stable remains a bottleneck for studies of many biological systems. The application ... Full text Link to item Cite

High-resolution protein structure determination starting with a global fold calculated from exact solutions to the RDC equations.

Journal Article J Biomol NMR · November 2009 We present a novel structure determination approach that exploits the global orientational restraints from RDCs to resolve ambiguous NOE assignments. Unlike traditional approaches that bootstrap the initial fold from ambiguous NOE assignments, we start by ... Full text Link to item Cite

Uridine-based inhibitors as new leads for antibiotics targeting Escherichia coli LpxC.

Journal Article Biochemistry · April 14, 2009 The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC catalyzes the committed reaction of lipid A (endotoxin) biosynthesis in Gram-negative bacteria and is a validated antibiotic target. Although several previously described compounds bind to ... Full text Link to item Cite

High resolution 4-D spectroscopy with sparse concentric shell sampling and FFT-CLEAN.

Journal Article J Biomol NMR · December 2008 Recent efforts to reduce the measurement time for multidimensional NMR experiments have fostered the development of a variety of new procedures for sampling and data processing. We recently described concentric ring sampling for 3-D NMR experiments, which ... Full text Link to item Cite

Mechanism and inhibition of LpxC: an essential zinc-dependent deacetylase of bacterial lipid A synthesis.

Journal Article Curr Pharm Biotechnol · February 2008 Multi-drug resistant (MDR), pathogenic Gram-negative bacteria pose a serious health threat, and novel antibiotic targets must be identified to combat MDR infections. One promising target is the zinc-dependent metalloamidase UDP-3-O-(R-3-hydroxymyristoyl)-N ... Full text Link to item Cite

A HAUSDORFF-BASED NOE ASSIGNMENT ALGORITHM USING PROTEIN BACKBONE DETERMINED FROM RESIDUAL DIPOLAR COUPLINGS AND ROTAMER PATTERNS.

Journal Article Comput Syst Bioinformatics Conf · 2008 High-throughput structure determination based on solution Nuclear Magnetic Resonance (NMR) spectroscopy plays an important role in structural genomics. One of the main bottlenecks in NMR structure determination is the interpretation of NMR data to obtain a ... Link to item Cite

A Hausdorff-based NOE assignment algorithm using protein backbone determined from residual dipolar couplings and rotamer patterns.

Journal Article Comput Syst Bioinformatics Conf · 2008 High-throughput structure determination based on solution Nuclear Magnetic Resonance (NMR) spectroscopy plays an important role in structural genomics. One of the main bottlenecks in NMR structure determination is the interpretation of NMR data to obtain a ... Link to item Cite

The ADAM10 prodomain is a specific inhibitor of ADAM10 proteolytic activity and inhibits cellular shedding events.

Journal Article J Biol Chem · December 7, 2007 ADAM10 is a disintegrin metalloproteinase that processes amyloid precursor protein and ErbB ligands and is involved in the shedding of many type I and type II single membrane-spanning proteins. Like tumor necrosis factor-alpha-converting enzyme (TACE or AD ... Full text Link to item Cite

Structure of the deacetylase LpxC bound to the antibiotic CHIR-090: Time-dependent inhibition and specificity in ligand binding.

Journal Article Proc Natl Acad Sci U S A · November 20, 2007 The UDP-3-O-(R-3-hydroxyacyl)-N-acetylglucosamine deacetylase LpxC is an essential enzyme of lipid A biosynthesis in Gram-negative bacteria and a promising antibiotic target. CHIR-090, the most potent LpxC inhibitor discovered to date, displays two-step ti ... Full text Link to item Cite

Drosophila PIWI associates with chromatin and interacts directly with HP1a.

Journal Article Genes Dev · September 15, 2007 The interface between cellular systems involving small noncoding RNAs and epigenetic change remains largely unexplored in metazoans. RNA-induced silencing systems have the potential to target particular regions of the genome for epigenetic change by locati ... Full text Link to item Cite

Solution structure of the Ubp-M BUZ domain, a highly specific protein module that recognizes the C-terminal tail of free ubiquitin.

Journal Article J Mol Biol · July 6, 2007 The BUZ/Znf-UBP domain is a distinct ubiquitin-binding module found in the cytoplasmic deacetylase HDAC6, the E3 ubiquitin ligase BRAP2/IMP, and a subfamily of deubiquitinating enzymes. Here, we report the solution structure of the BUZ domain of Ubp-M, a u ... Full text Link to item Cite

The low affinity IgE receptor (CD23) is cleaved by the metalloproteinase ADAM10.

Journal Article J Biol Chem · May 18, 2007 The low affinity IgE receptor, FcepsilonRII (CD23), is both a positive and negative regulator of IgE synthesis. The proteinase activity that converts the membrane-bound form of CD23 into a soluble species (sCD23) is an important regulator of the function o ... Full text Link to item Cite

Inhibition of lipid A biosynthesis as the primary mechanism of CHIR-090 antibiotic activity in Escherichia coli.

Journal Article Biochemistry · March 27, 2007 The deacetylation of UDP-3-O-[(R)-3-hydroxymyristoyl]-N-acetylglucosamine (UDP-3-O-acyl-GlcNAc) by LpxC is the committed reaction of lipid A biosynthesis. CHIR-090, a novel N-aroyl-l-threonine hydroxamic acid, is a potent, slow, tight-binding inhibitor of ... Full text Link to item Cite

Structure of the ubiquitin-binding zinc finger domain of human DNA Y-polymerase eta.

Journal Article EMBO Rep · March 2007 The ubiquitin-binding zinc finger (UBZ) domain of human DNA Y-family polymerase (pol) eta is important in the recruitment of the polymerase to the stalled replication machinery in translesion synthesis. Here, we report the solution structure of the pol eta ... Full text Link to item Cite

Sampling of the NMR time domain along concentric rings.

Journal Article J Magn Reson · February 2007 We present a novel approach to sampling the NMR time domain, whereby the sampling points are aligned on concentric rings, which we term concentric ring sampling (CRS). Radial sampling constitutes a special case of CRS where each ring has the same number of ... Full text Link to item Cite

Polar Fourier transforms of radially sampled NMR data.

Journal Article J Magn Reson · September 2006 Radial sampling of the NMR time domain has recently been introduced to speed up data collection significantly. Here, we show that radially sampled data can be processed directly using Fourier transforms in polar coordinates. We present a comprehensive theo ... Full text Link to item Cite

A 'just-in-time' HN(CA)CO experiment for the backbone assignment of large proteins with high sensitivity.

Journal Article J Magn Reson · July 2006 Among the suite of commonly used backbone experiments, HNCACO presents an unresolved sensitivity limitation due to fast 13CO transverse relaxation and passive 13Calpha-13Cbeta coupling. Here, we present a high-sensitivity 'just-in-time' (JIT) HN(CA)CO puls ... Full text Link to item Cite

PR-CALC: a program for the reconstruction of NMR spectra from projections.

Journal Article J Biomol NMR · March 2006 Projection-reconstruction NMR (PR-NMR) has attracted growing attention as a method for collecting multidimensional NMR data rapidly. The PR-NMR procedure involves measuring lower-dimensional projections of a higher-dimensional spectrum, which are then used ... Full text Link to item Cite

Evaluating the quality of NMR structures by local density of protons.

Journal Article Proteins · March 1, 2006 Evaluating the quality of experimentally determined protein structural models is an essential step toward identifying potential errors and guiding further structural refinement. Herein, we report the use of proton local density as a sensitive measure to as ... Full text Link to item Cite

Solution structure of the Set2-Rpb1 interacting domain of human Set2 and its interaction with the hyperphosphorylated C-terminal domain of Rpb1.

Journal Article Proc Natl Acad Sci U S A · December 6, 2005 The phosphorylation state of the C-terminal repeat domain (CTD) of the largest subunit of RNA polymerase II changes as polymerase transcribes a gene, and the distinct forms of the phospho-CTD (PCTD) recruit different nuclear factors to elongating polymeras ... Full text Link to item Cite

A methylation-dependent electrostatic switch controls DNA repair and transcriptional activation by E. coli ada.

Journal Article Mol Cell · October 7, 2005 The transcriptional activity of many sequence-specific DNA binding proteins is directly regulated by posttranslational covalent modification. Although this form of regulation was first described nearly two decades ago, it remains poorly understood at a mec ... Full text Link to item Cite

Filtered backprojection for the reconstruction of a high-resolution (4,2)D CH3-NH NOESY spectrum on a 29 kDa protein.

Journal Article J Am Chem Soc · August 24, 2005 Projection-reconstruction (PR) NMR enables rapid collection of multidimensional NMR data. NOESY represents a particularly difficult challenge for currently existing reconstruction algorithms, as it requires the quantitative reconstruction of an unknown num ... Full text Link to item Cite

Rapid assignment of protein side chain resonances using projection-reconstruction of (4,3)D HC(CCO)NH and intra-HC(C)NH experiments.

Journal Article J Magn Reson · July 2005 The reconstruction of higher-dimensional NMR spectra from projections can provide significant savings in instrument time. Here, we demonstrate its application to the (4,3)D HC(CCO)NH and intra-HC(C)NH experiments. The latter experiment contains a novel int ... Full text Link to item Cite

(4,2)D Projection--reconstruction experiments for protein backbone assignment: application to human carbonic anhydrase II and calbindin D(28K).

Journal Article J Am Chem Soc · June 22, 2005 Projection-reconstruction NMR experiments have been shown to significantly reduce the acquisition time required to obtain protein backbone assignment data. To date, this concept has only been applied to smaller (15)N/(13)C-labeled proteins. Here, we show t ... Full text Link to item Cite

Kinetic analysis of the zinc-dependent deacetylase in the lipid A biosynthetic pathway.

Journal Article Biochemistry · February 1, 2005 Featured Publication The first committed step of lipid A biosynthesis in Gram-negative bacteria is catalyzed by the zinc-dependent hydrolase LpxC that removes an acetate from the nitrogen at the 2' '-position of UDP-3-O-acyl-N-acetylglucosamine. Recent structural characterizat ... Full text Link to item Cite

Refined solution structure of the LpxC-TU-514 complex and pKa analysis of an active site histidine: insights into the mechanism and inhibitor design.

Journal Article Biochemistry · February 1, 2005 Featured Publication Lipopolysaccharide, the major constituent of the outer monolayer of the outer membrane of Gram-negative bacteria, is anchored into the membrane through the hydrophobic moiety lipid A, a hexaacylated disaccharide. The zinc-dependent metalloamidase UDP-3-O-a ... Full text Link to item Cite

Generalized reconstruction of n-D NMR spectra from multiple projections: application to the 5-D HACACONH spectrum of protein G B1 domain.

Journal Article J Am Chem Soc · February 4, 2004 Featured Publication Reconstructing multidimensional NMR spectra from 2-D projections significantly reduces the time needed for data collection over conventional methodology. Here, we provide a generalization of the projection-reconstruction process to spectra of arbitrary dim ... Full text Link to item Cite

Structure of the LpxC deacetylase with a bound substrate-analog inhibitor.

Journal Article Nat Struct Biol · August 2003 Featured Publication The zinc-dependent UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) catalyzes the first committed step in the biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide (LPS) that constitutes the outermost monolayer of Gram-negative bacteria. ... Full text Link to item Cite

PACES: Protein sequential assignment by computer-assisted exhaustive search.

Journal Article J Biomol NMR · June 2003 Featured Publication A crucial step in determining solution structures of proteins using nuclear magnetic resonance (NMR) spectroscopy is the process of sequential assignment, which correlates backbone resonances to corresponding residues in the primary sequence of a protein, ... Full text Link to item Cite

Characteristics of the interaction of a synthetic human tristetraprolin tandem zinc finger peptide with AU-rich element-containing RNA substrates.

Journal Article J Biol Chem · May 30, 2003 Featured Publication Tristetraprolin (TTP) and its two known mammalian family members are tandem CCCH zinc finger proteins that can bind to AU-rich elements (AREs) in cellular mRNAs and destabilize those transcripts, apparently by initiating their deadenylation. Previous studi ... Full text Link to item Cite

A novel approach for characterizing protein ligand complexes: molecular basis for specificity of small-molecule Bcl-2 inhibitors.

Journal Article J Am Chem Soc · February 20, 2002 The increasing diversity of small molecule libraries has been an important source for the development of new drugs and, more recently, for unraveling the mechanisms of cellular events-a process termed chemical genetics.(1) Unfortunately, the majority of cu ... Full text Link to item Cite

Solution structure of DFF40 and DFF45 N-terminal domain complex and mutual chaperone activity of DFF40 and DFF45.

Journal Article Proc Natl Acad Sci U S A · May 22, 2001 Featured Publication Apoptotic DNA fragmentation is mediated by a caspase-activated DNA fragmentation factor (DFF)40. Expression and folding of DFF40 require the presence of DFF45, which also acts as a nuclease inhibitor before DFF40 activation by execution caspases. The N-ter ... Full text Link to item Cite

A solubility-enhancement tag (SET) for NMR studies of poorly behaving proteins.

Journal Article J Biomol NMR · May 2001 Featured Publication Protein-fusion constructs have been used with great success for enhancing expression of soluble recombinant protein and as tags for affinity purification. Unfortunately the most popular tags, such as GST and MBP, are large, which hinders direct NMR studies ... Full text Link to item Cite

Solution structure of the CIDE-N domain of CIDE-B and a model for CIDE-N/CIDE-N interactions in the DNA fragmentation pathway of apoptosis.

Journal Article Cell · December 23, 1999 Featured Publication Apoptotic DNA fragmentation and chromatin condensation are mediated by the caspase-activated DFF40/ CAD nuclease, which is chaperoned and inhibited by DFF45/ICAD. CIDE proteins share a homologous regulatory CIDE-N domain with DFF40/CAD and DFF45/ ICAD. Her ... Full text Link to item Cite

Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: a structural basis for specific adaptor/caspase interaction.

Journal Article Proc Natl Acad Sci U S A · September 28, 1999 Featured Publication Direct recruitment and activation of caspase-9 by Apaf-1 through the homophilic CARD/CARD (Caspase Recruitment Domain) interaction is critical for the activation of caspases downstream of mitochondrial damage in apoptosis. Here we report the solution struc ... Full text Link to item Cite

Solution structure of the core NFATC1/DNA complex.

Journal Article Cell · March 6, 1998 Featured Publication The nuclear factor of the activated T cell (NFAT) family of transcription factors regulates cytokine gene expression by binding to the promoter/enhancer regions of antigen-responsive genes, usually in cooperation with heterologous DNA-binding partners. Her ... Full text Link to item Cite

Unusual Rel-like architecture in the DNA-binding domain of the transcription factor NFATc.

Journal Article Nature · January 9, 1997 Featured Publication Transcription factors of the NFAT family regulate the production of effector proteins that coordinate the immune response. The immunosuppressive drugs FK506 and cyclosporin A (CsA) act by blocking a Ca2+-mediated signalling pathway leading to NFAT. Althoug ... Full text Link to item Cite