Journal ArticleNat Chem Biol · December 2024
G-protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small-molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often l ...
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Journal ArticleEBioMedicine · December 2024
BACKGROUND: Pulmonary fibrosis is a challenging clinical problem with lung pathology featuring immune cell infiltrates, fibroblast expansion, and matrix deposition. Molecular analysis of diseased lungs and preclinical models have uncovered C-C chemokine re ...
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Journal ArticleBr J Pharmacol · September 11, 2024
Class A G protein-coupled receptors (GPCRs) continue to garner interest for their essential roles in cell signalling and their importance as drug targets. Although numerous drugs in the clinic target these receptors, over 60% GPCRs remain unexploited. More ...
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Journal ArticleSci Signal · August 13, 2024
Different ligands stabilize specific conformations of the angiotensin II type 1 receptor (AT1R) that direct distinct signaling cascades mediated by heterotrimeric G proteins or β-arrestin. These different active conformations are thought to engage distinct ...
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Journal ArticleMol Pharmacol · February 15, 2024
Dualsteric G protein-coupled receptor (GPCR) ligands are a class of bitopic ligands that consist of an orthosteric pharmacophore, which binds to the pocket occupied by the receptor's endogenous agonist, and an allosteric pharmacophore, which binds to a dis ...
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Journal ArticlebioRxiv · August 24, 2023
G protein-coupled receptors (GPCRs) are key regulators of human physiology and are the targets of many small molecule research compounds and therapeutic drugs. While most of these ligands bind to their target GPCR with high affinity, selectivity is often l ...
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Journal ArticleJ Cardiovasc Pharmacol · September 1, 2022
Understanding the activation of G protein-coupled receptors (GPCRs) is of paramount importance to the field of cardiovascular medicine due to the critical physiological roles of these receptors and their prominence as drug targets. Although many cardiovasc ...
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Journal ArticleNat Chem Biol · October 2021
The predominant approach for antibody generation remains animal immunization, which can yield exceptionally selective and potent antibody clones owing to the powerful evolutionary process of somatic hypermutation. However, animal immunization is inherently ...
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Journal ArticlebioRxiv · November 11, 2020
The predominant approach for antibody generation remains animal immunization, which can yield exceptionally selective and potent antibody clones owing to the powerful evolutionary process of somatic hypermutation. However, animal immunization is inherently ...
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Journal ArticleTrends Cell Biol · September 2020
G protein-coupled receptors (GPCRs) are privileged structural scaffolds in biology that have the versatility to regulate diverse physiological processes. Interestingly, many GPCR ligands exhibit significant 'bias' - the ability to preferentially activate s ...
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Journal ArticleProc Natl Acad Sci U S A · August 18, 2020
There is considerable interest in developing antibodies as functional modulators of G protein-coupled receptor (GPCR) signaling for both therapeutic and research applications. However, there are few antibody ligands targeting GPCRs outside of the chemokine ...
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ConferenceThe FASEB Journal · April 2020
Nanobodies are single‐domain antibody fragments that are derived from camelids and used extensively as research tools. Despite their usefulness, traditional immunization‐based approaches for generating nanobodies have proven ineffective for produci ...
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Journal ArticleNature · March 2020
After activation by an agonist, G-protein-coupled receptors (GPCRs) recruit β-arrestin, which desensitizes heterotrimeric G-protein signalling and promotes receptor endocytosis1. Additionally, β-arrestin directly regulates many cell signalling pathways tha ...
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Journal ArticleScience · February 21, 2020
Biased signaling, in which different ligands that bind to the same G protein-coupled receptor preferentially trigger distinct signaling pathways, holds great promise for the design of safer and more effective drugs. Its structural mechanism remains unclear ...
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Journal ArticleScience · February 21, 2020
Biased agonists of G protein-coupled receptors (GPCRs) preferentially activate a subset of downstream signaling pathways. In this work, we present crystal structures of angiotensin II type 1 receptor (AT1R) (2.7 to 2.9 angstroms) bound to three ligands wit ...
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Journal ArticleJ Biol Chem · September 6, 2019
A hallmark of G-protein-coupled receptors (GPCRs) is the conversion of external stimuli into specific cellular responses. In this tightly-regulated process, extracellular ligand binding by GPCRs promotes specific conformational changes within the seven tra ...
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Journal ArticleCell · January 24, 2019
The angiotensin II (AngII) type 1 receptor (AT1R) is a critical regulator of cardiovascular and renal function and is an important model for studies of G-protein-coupled receptor (GPCR) signaling. By stabilizing the receptor with a single-domain antibody f ...
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Journal ArticleCell · January 24, 2019
"Biased" G protein-coupled receptor (GPCR) agonists preferentially activate pathways mediated by G proteins or β-arrestins. Here, we use double electron-electron resonance spectroscopy to probe the changes that ligands induce in the conformational distribu ...
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Journal ArticleSci Signal · August 21, 2018
Biased agonists of G protein-coupled receptors (GPCRs), which selectively activate either G protein- or β-arrestin-mediated signaling pathways, are of major therapeutic interest because they have the potential to show improved efficacy and specificity as d ...
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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 ArticleProc Natl Acad Sci U S A · April 10, 2018
The ability of G protein-coupled receptors (GPCRs) to initiate complex cascades of cellular signaling is governed by the sequential coupling of three main transducer proteins, G protein, GPCR kinase (GRK), and β-arrestin. Mounting evidence indicates these ...
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Journal ArticleCell · April 6, 2017
G-protein-coupled receptors (GPCRs) play critical roles in regulating physiological processes ranging from neurotransmission to cardiovascular function. Current methods for tracking GPCR signaling suffer from low throughput, modification or overexpression ...
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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 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 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 ArticleMol Pharmacol · March 2014
The biologic activity induced by ligand binding to orthosteric or allosteric sites on a G protein-coupled receptor (GPCR) is mediated by stabilization of specific receptor conformations. In the case of the β2 adrenergic receptor, these ligands are generall ...
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Journal ArticleBiotechnol J · December 2013
The yeast three-hybrid (Y3H) assay expands the fields of drug discovery and protein engineering by enabling the search of large variant libraries for targets that do not inherently produce a distinct, measurable phenotype. The Y3H assay links the DNA-bindi ...
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ConferenceBlood · November 15, 2013
AbstractBackgroundChronic myeloid leukemia (CML) is a myeloproliferative neoplasm of hematopoietic stem cells characterized by presenc ...
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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 ArticleMethods Mol Biol · 2013
While mutagenesis of single genes is now common practice in molecular biology, engineering multiple target genes still requires complex cloning techniques and thus is limited to expert laboratories. Here, we describe "Reiterative Recombination," a user-fri ...
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Journal ArticleProc Natl Acad Sci U S A · September 13, 2011
The increasing sophistication of synthetic biology is creating a demand for robust, broadly accessible methodology for constructing multigene pathways inside of the cell. Due to the difficulty of rationally designing pathways that function as desired in vi ...
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