The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: May 10, 2022

Abstract G-protein-coupled receptors do not only feature the orthosteric pockets, where most endogenous agonists bind, but also a multitude of other allosteric pockets that have come into focus as potential binding sites for synthetic modulators. Here, to better characterise such we investigate 557 GPCR structures by exhaustively docking small molecular probes in silico and converting ensemble locations pocket-defining volumes. Our analysis confirms all previously identified reveals nine untargeted sites. In order test feasibility functional modulation through ligand sites, mutate residues two model receptors, muscarinic acetylcholine receptor M 3 β 2 -adrenergic receptor. Moreover, analyse correlation inter-residue contacts with activation states show contact patterns closely correlating indeed coincide these

Language: Английский

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G protein-coupled receptors in neurodegenerative diseases and psychiatric disorders

Signal Transduction and Targeted Therapy, Journal Year: 2023, Volume and Issue: 8(1)

Published: May 3, 2023

Neuropsychiatric disorders are multifactorial with diverse aetiological factors. Identifying treatment targets is challenging because the diseases resulting from heterogeneous biological, genetic, and environmental Nevertheless, increasing understanding of G protein-coupled receptor (GPCR) opens a new possibility in drug discovery. Harnessing our knowledge molecular mechanisms structural information GPCRs will be advantageous for developing effective drugs. This review provides an overview role various neurodegenerative psychiatric diseases. Besides, we highlight emerging opportunities novel GPCR address recent progress development.

Language: Английский

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Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways

Nature Communications, Journal Year: 2025, Volume and Issue: 16(1)

Published: Feb. 27, 2025

G protein-coupled receptors (GPCRs) constitute a functionally diverse protein family and are targets for broad spectrum of pharmaceuticals. Technological progress in X-ray crystallography cryogenic electron microscopy has enabled extensive, high-resolution structural characterisation GPCRs different conformational states. However, as highly dynamic events underlie GPCR signalling, complete understanding functionality requires insights into their dynamics. Here, we present large dataset molecular dynamics simulations covering 60% currently available structures. Our analysis reveals extensive local "breathing" motions the receptor on nano- to microsecond timescale provides access numerous previously unexplored Furthermore, reveal that flexibility impacts shape allosteric drug binding sites, which frequently adopt partially or completely closed states absence modulator. We demonstrate exploring membrane lipid interaction with is an efficient approach expose such hidden sites even lateral ligand entrance gateways. The obtained generated conformations, gates allows us better understand these opens new therapeutic avenues drug-targeting strategies. critical signal transmission cell. authors probe plasticity using simulations, enabling detection entry gateways range types.

Language: Английский

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Structural basis of GPCR coupling to distinct signal transducers: implications for biased signaling

Trends in Biochemical Sciences, Journal Year: 2022, Volume and Issue: 47(7), P. 570 - 581

Published: April 5, 2022

Language: Английский

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The structure and function of olfactory receptors

Trends in Pharmacological Sciences, Journal Year: 2024, Volume and Issue: 45(3), P. 268 - 280

Published: Jan. 31, 2024

Language: Английский

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New Insights into the Structure and Function of Class B1 GPCRs

Endocrine Reviews, Journal Year: 2022, Volume and Issue: 44(3), P. 492 - 517

Published: Dec. 22, 2022

Abstract G protein–coupled receptors (GPCRs) are the largest family of cell surface receptors. Class B1 GPCRs constitute a subfamily 15 that characteristically contain large extracellular domains (ECDs) and respond to long polypeptide hormones. critical regulators homeostasis, and, as such, many important drug targets. While most transmembrane proteins, including GPCRs, recalcitrant crystallization, recent advances in cryo-electron microscopy (cryo-EM) have facilitated rapid expansion structural understanding membrane proteins. As testament this success, structures for all class bound proteins been determined by cryo-EM past 5 years. Further uncovered dynamics these receptors, ligands, signaling partners. Here, we examine underpinnings with an emphasis on structure–function relationships.

Language: Английский

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Allosteric modulation of GPCRs: From structural insights to in silico drug discovery

Pharmacology & Therapeutics, Journal Year: 2022, Volume and Issue: 237, P. 108242 - 108242

Published: July 18, 2022

Language: Английский

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Ligands selectively tune the local and global motions of neurotensin receptor 1 (NTS1)

Cell Reports, Journal Year: 2023, Volume and Issue: 42(1), P. 112015 - 112015

Published: Jan. 1, 2023

Nuclear magnetic resonance (NMR) studies have revealed that fast methyl sidechain dynamics can report on entropically-driven allostery. Yet, NMR applications been largely limited to the super-microsecond motional regimes of G protein-coupled receptors (GPCRs). We use 13Cε-methionine chemical shift-based global order parameters test if ligands affect a thermostabilized GPCR, neurotensin receptor 1 (NTS1). establish NTS1 solution ensemble includes substates with lifetimes several, discrete timescales. The longest-lived states reflect those captured in agonist- and inverse agonist-bound crystal structures, separated by large energy barriers. observe rapid fluctuations individual methionine residues, superimposed these long-lived states, respond collectively degree fast, correlating ligand pharmacology. This approach lends confidence interpreting spectra terms local structure dihedral angle geometry. results suggest role for sub-microsecond conformational entropy GPCR discrimination.

Language: Английский

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Genome-wide pan-GPCR cell libraries accelerate drug discovery

Acta Pharmaceutica Sinica B, Journal Year: 2024, Volume and Issue: 14(10), P. 4296 - 4311

Published: June 26, 2024

G protein-coupled receptors (GPCRs) are pivotal in mediating diverse physiological and pathological processes, rendering them promising targets for drug discovery. GPCRs account about 40% of FDA-approved drugs, representing the most successful targets. However, only approximately 15% 800 human targeted by market leaving numerous opportunities discovery among remaining receptors. Cell expression systems play crucial roles GPCR field, including novel target identification, structural functional characterization, potential ligand screening, signal pathway elucidation, safety evaluation. Here, we discuss principles, applications, limitations widely used cell GPCR-targeted discovery, function investigation, pharmacological property studies. We also propose three strategies constructing genome-wide pan-GPCR libraries, which will provide a powerful platform facilitate study mechanisms evaluation, ultimately accelerating process

Language: Английский

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Elucidation of a dynamic interplay between a beta-2 adrenergic receptor, its agonist, and stimulatory G protein

Proceedings of the National Academy of Sciences, Journal Year: 2023, Volume and Issue: 120(10)

Published: Feb. 28, 2023

G protein-coupled receptors (GPCRs) represent the largest group of membrane for transmembrane signal transduction. Ligand-induced activation GPCRs triggers protein followed by various signaling cascades. Understanding structural and energetic determinants ligand binding to proteins is crucial design pharmacological treatments targeting specific conformations these precisely control their properties. In this study, we focused on interactions a prototypical GPCR, beta-2 adrenergic receptor (β 2 AR), with its endogenous agonist, norepinephrine (NE), stimulatory (G s ). Using molecular dynamics (MD) simulations, demonstrated stabilization cationic NE, NE(+), β AR recruitment, in line experimental observations. We also captured partial dissociation from conformational interconversions between closed open NE(+)–β AR–G ternary complex while it still bound receptor. The variation NE(+) poses was found alter α subunit α) transitions. Our simulations showed that interdomain movement stacking α1 α5 helices are significant increasing distance AR, which may indicate increase commences when predominantly an state can be triggered intracellular loop 3 (ICL3) interacting α, causing changes helix. results help explain mechanisms GPCR-mediated modulation activation.

Language: Английский

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