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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Dual Function of the Third Component in Ternary Organic Solar Cells: Broaden the Spectrum and Optimize the Morphology

Small, Journal Year: 2024, Volume and Issue: 20(24)

Published: Jan. 29, 2024

Abstract Ternary organic solar cells (T‐OSCs) have attracted significant attention as high‐performance devices. In recent years, T‐OSCs achieved remarkable progress with power conversion efficiency (PCE) exceeding 19%. However, the introduction of third component complicates intermolecular interaction compared to binary blend, resulting in poor controllability active layer and limiting performance improvement. To address these issues, dual‐functional components been developed that not only broaden spectral range but also optimize morphology. this review, effect on expanding absorption is first discussed. Second, extra functions are introduced, including adjusting crystallinity molecular stack layer, regulating phase separation purity, altering orientation donor or acceptor. Finally, a summary current research provided, followed by discussion future directions.

Language: Английский

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Homodimerization of CB2 cannabinoid receptor triggered by a bivalent ligand enhances cellular signaling

Pharmacological Research, Journal Year: 2024, Volume and Issue: 208, P. 107363 - 107363

Published: Aug. 23, 2024

G protein-coupled receptors (GPCRs) exist within a landscape of interconvertible conformational states and in dynamic equilibrium between monomers higher-order oligomers, both influenced by ligand binding. Here, we show that homobivalent formed equal chromenopyrazole moieties as pharmacophores, connected 14 methylene units, can modulate the dynamics cannabinoid CB

Language: Английский

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Allosteric drugs: New principles and design approaches

Current Opinion in Structural Biology, Journal Year: 2024, Volume and Issue: 84, P. 102758 - 102758

Published: Jan. 2, 2024

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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Allosteric Regulation of G-Protein-Coupled Receptors: From Diversity of Molecular Mechanisms to Multiple Allosteric Sites and Their Ligands

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(7), P. 6187 - 6187

Published: March 24, 2023

Allosteric regulation is critical for the functioning of G protein-coupled receptors (GPCRs) and their signaling pathways. Endogenous allosteric regulators GPCRs are simple ions, various biomolecules, protein components GPCR (G proteins β-arrestins). The stability functional activity complexes also due to multicenter interactions between protomers. complexity effects caused by numerous differing in structure, availability, mechanisms action predetermines multiplicity different topology sites GPCRs. These can be localized extracellular loops; inside transmembrane tunnel its upper lower vestibules; cytoplasmic on outer, membrane-contacting surface domain. They involved basal orthosteric agonist-stimulated receptor activity, biased agonism, GPCR-complex formation, endocytosis. targets a large number synthetic modulators, including those constructed using molecular docking. review devoted principles regulation, topology, endogenous regulators, autoantibodies pepducins. chemokine receptors, proteinase-activated thyroid-stimulating luteinizing hormone beta-adrenergic described more detail.

Language: Английский

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A µ-opioid receptor modulator that works cooperatively with naloxone

Nature, Journal Year: 2024, Volume and Issue: 631(8021), P. 686 - 693

Published: July 3, 2024

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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Design and structural validation of peptide–drug conjugate ligands of the kappa-opioid receptor

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: Dec. 6, 2023

Despite the increasing number of GPCR structures and recent advances in peptide design, development efficient technologies allowing rational design high-affinity ligands for single GPCRs remains an unmet challenge. Here, we develop a computational approach designing conjugates lariat-shaped macrocyclized peptides small molecule opioid ligand. We demonstrate its feasibility by discovering chemical scaffolds kappa-opioid receptor (KOR) with desired pharmacological activities. The designed De Novo Cyclic Peptide (DNCP)-β-naloxamine (NalA) exhibit vitro potent mixed KOR agonism/mu-opioid (MOR) antagonism, nanomolar binding affinity, selectivity, efficacy bias at KOR. Proof-of-concept vivo studies that DNCP-β-NalA(1) induces KOR-mediated antinociception male mice. high-resolution cryo-EM structure (2.6 Å) DNCP-β-NalA-KOR-Gi1 complex molecular dynamics simulations are harnessed to validate model. This reveals network residues ECL2/3 TM6/7 controlling intrinsic In general, our de novo platform overcomes extensive lead optimization encountered ultra-large library docking virtual screening campaigns offers innovation ligand discovery. may drive next-generation therapeutics medical applications such as pain conditions.

Language: Английский

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Relevance of G protein‐coupled receptor (GPCR) dynamics for receptor activation, signalling bias and allosteric modulation

British Journal of Pharmacology, Journal Year: 2024, Volume and Issue: unknown

Published: July 8, 2024

Abstract G protein‐coupled receptors (GPCRs) are one of the major drug targets. In recent years, computational design for GPCRs has mainly focused on static structures obtained through X‐ray crystallography, cryogenic electron microscopy (cryo‐EM) or in silico modelling as a starting point virtual screening campaigns. However, highly flexible entities with ability to adopt different conformational states that elicit physiological responses. Including this knowledge discovery pipeline can help tailor novel conformation‐specific drugs an improved therapeutic profile. review, we outline our current about GPCR dynamics is relevant receptor activation, signalling bias and allosteric modulation. Ultimately, highlight new technological implementations such time‐resolved crystallography cryo‐EM well algorithms contribute more comprehensive understanding its relevance functionality.

Language: Английский

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