Journal ArticleCommun Biol · July 7, 2024
Classically, G protein-coupled receptors (GPCRs) promote signaling at the plasma membrane through activation of heterotrimeric Gαβγ proteins, followed by the recruitment of GPCR kinases and βarrestin (βarr) to initiate receptor desensitization and internal ...
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Journal ArticleProc Natl Acad Sci U S A · October 24, 2023
β-arrestins are multivalent adaptor proteins that bind active phosphorylated G protein-coupled receptors (GPCRs) to inhibit G protein signaling, mediate receptor internalization, and initiate alternative signaling events. β-arrestins link agonist-stimulate ...
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Journal ArticleJ Clin Invest · September 15, 2023
Asthma is a chronic inflammatory disease associated with episodic airway narrowing. Inhaled β2-adrenergic receptor (β2AR) agonists (β2-agonists) promote - with limited efficacy - bronchodilation in asthma. All β2-agonists are canonical orthosteric ligands ...
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Journal ArticleCell · May 12, 2022
β-arrestins bind G protein-coupled receptors to terminate G protein signaling and to facilitate other downstream signaling pathways. Using single-molecule fluorescence resonance energy transfer imaging, we show that β-arrestin is strongly autoinhibited in ...
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Journal ArticleMol Pharmacol · December 2021
β 1 adrenergic receptors (β 1ARs) are central regulators of cardiac function and a drug target for cardiac disease. As a member of the G protein-coupled receptor family, β 1ARs activate cellular signaling by primarily coupling to Gs proteins to activate ad ...
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Journal ArticleJ Biol Chem · December 2021
G protein-coupled receptors (GPCRs) convert external stimuli into cellular signals through heterotrimeric guanine nucleotide-binding proteins (G-proteins) and β-arrestins (βarrs). In a βarr-dependent signaling pathway, βarrs link GPCRs to various downstrea ...
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Journal ArticleMol Pharmacol · November 2021
Among β-blockers that are clinically prescribed for heart failure, carvedilol is a first-choice agent with unique pharmacological properties. Carvedilol is distinct from other β-blockers in its ability to elicit β-arrestin-biased agonism, which has been su ...
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Journal ArticleScience · March 12, 2021
Heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) are common drug targets and canonically couple to specific Gα protein subtypes and β-arrestin adaptor proteins. G protein-mediated signaling and β-arrestin-mediated sig ...
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Journal ArticleNat Commun · September 25, 2020
Characterization of the dynamic conformational changes in membrane protein signaling complexes by nuclear magnetic resonance (NMR) spectroscopy remains challenging. Here we report the site-specific incorporation of 4-trimethylsilyl phenylalanine (TMSiPhe) ...
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Journal ArticleScience · June 28, 2019
Drugs targeting the orthosteric, primary binding site of G protein-coupled receptors are the most common therapeutics. Allosteric binding sites, elsewhere on the receptors, are less well-defined, and so less exploited clinically. We report the crystal stru ...
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Journal ArticleMol Pharmacol · August 2018
Conventional drug discovery efforts at the β2-adrenoceptor (β2AR) have led to the development of ligands that bind almost exclusively to the receptor's hormone-binding orthosteric site. However, targeting the largely unexplored and evolutionarily unique al ...
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Journal ArticleBioorg Med Chem · May 15, 2018
The β2-adrenergic receptor (β2AR), a G protein-coupled receptor, is an important therapeutic target. We recently described Cmpd-15, the first small molecule negative allosteric modulator (NAM) for the β2AR. Herein we report in details the design, synthesis ...
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Journal ArticleElife · February 2, 2018
Luminal fluid reabsorption plays a fundamental role in male fertility. We demonstrated that the ubiquitous GPCR signaling proteins Gq and β-arrestin-1 are essential for fluid reabsorption because they mediate coupling between an orphan receptor ADGRG2 (GPR ...
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Journal ArticleNature · August 24, 2017
G-protein-coupled receptors (GPCRs) pose challenges for drug discovery efforts because of the high degree of structural homology in the orthosteric pocket, particularly for GPCRs within a single subfamily, such as the nine adrenergic receptors. Allosteric ...
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Journal ArticleBiol Psychiatry · April 15, 2017
BACKGROUND: Stress is a conserved physiological response in mammals. Whereas moderate stress strengthens memory to improve reactions to previously experienced difficult situations, too much stress is harmful. METHODS: We used specific β-adrenergic agonists ...
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Journal ArticleProc Natl Acad Sci U S A · March 7, 2017
β-Arrestins (βarrs) interact with G protein-coupled receptors (GPCRs) to desensitize G protein signaling, to initiate signaling on their own, and to mediate receptor endocytosis. Prior structural studies have revealed two unique conformations of GPCR-βarr ...
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Journal ArticleProc Natl Acad Sci U S A · February 14, 2017
The β2-adrenergic receptor (β2AR) has been a model system for understanding regulatory mechanisms of G-protein-coupled receptor (GPCR) actions and plays a significant role in cardiovascular and pulmonary diseases. Because all known β-adrenergic receptor dr ...
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Journal ArticleNat Commun · February 9, 2017
Acute hormone secretion triggered by G protein-coupled receptor (GPCR) activation underlies many fundamental physiological processes. GPCR signalling is negatively regulated by β-arrestins, adaptor molecules that also activate different intracellular signa ...
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Journal ArticleNat Chem Biol · September 2016
G-protein-coupled receptor (GPCR) ligands function by stabilizing multiple, functionally distinct receptor conformations. This property underlies the ability of 'biased agonists' to activate specific subsets of a given receptor's signaling profile. However ...
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Journal ArticleCell · August 11, 2016
Classically, G protein-coupled receptor (GPCR) stimulation promotes G protein signaling at the plasma membrane, followed by rapid β-arrestin-mediated desensitization and receptor internalization into endosomes. However, it has been demonstrated that some G ...
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Journal ArticleNature · July 21, 2016
G-protein-coupled receptors (GPCRs) modulate many physiological processes by transducing a variety of extracellular cues into intracellular responses. Ligand binding to an extracellular orthosteric pocket propagates conformational change to the receptor cy ...
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Journal ArticleNature · August 14, 2014
G-protein-coupled receptors (GPCRs) are critically regulated by β-arrestins, which not only desensitize G-protein signalling but also initiate a G-protein-independent wave of signalling. A recent surge of structural data on a number of GPCRs, including the ...
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Journal ArticleNat Protoc · 2014
An understanding of the mechanism accompanying functional conformational changes associated with protein activation has important implications for drug design. Here we describe a powerful method, conformational changes and dynamics using stable-isotope lab ...
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Journal ArticleACS Med Chem Lett · October 10, 2013
G-protein coupled receptors (GPCRs) are the primary target class of currently marketed drugs, accounting for about a quarter of all drug targets of approved medicines. However, almost all the screening efforts for novel ligand discovery rely exclusively on ...
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Journal ArticleChinese Journal of Organic Chemistry · March 1, 2013
BI-167107 is a new long-acting β2-adrenergic receptor (β2-AR) agonist, and has important application in determining the critical structures of receptor/ligand proteins complex of G-protein-coupled receptor (GPCR). By employing 2-nitroresorcinol as starting ...
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Journal ArticleNat Chem Biol · August 21, 2011
Seven-transmembrane receptors (7TMRs), also called G protein-coupled receptors (GPCRs), represent the largest class of drug targets, and they can signal through several distinct mechanisms including those mediated by G proteins and the multifunctional adap ...
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Journal ArticlePLoS One · November 24, 2010
BACKGROUND: Cucurbitacins are plant natural products that inhibit activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway by an unknown mechanism. They are also known to cause changes in the organization o ...
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Journal ArticleBiochim Biophys Acta · February 2010
Ezrin/radixin/moesin (ERM) proteins are membrane-cytoskeleton linkers that also have roles in signal transduction. Here we show that G protein-coupled receptor kinase 2 (GRK2) regulates membrane protrusion and cell migration during wound closure in Madin-D ...
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Journal ArticleJ Biol Chem · September 5, 2008
Cell migration is central to a number of normal and disease processes. Small organic molecules that inhibit cell migration have potential as both research probes and therapeutic agents. We have identified two tetrahydroisoquinoline natural product analogs ...
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Journal ArticleChem Biol · September 2006
In the course of screening for new small-molecule modulators of cell motility, we discovered that quinocarmycin (also known as quinocarcin) analog DX-52-1 is an inhibitor of epithelial cell migration. While it has been assumed that the main target of DX-52 ...
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