G-protein activation by a metabotropic glutamate receptor

Nature, Journal Year: 2021, Volume and Issue: 595(7867), P. 450 - 454

Published: June 30, 2021

Language: Английский

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Genetic association analysis of 77,539 genomes reveals rare disease etiologies

Nature Medicine, Journal Year: 2023, Volume and Issue: 29(3), P. 679 - 688

Published: March 1, 2023

Abstract The genetic etiologies of more than half rare diseases remain unknown. Standardized genome sequencing and phenotyping large patient cohorts provide an opportunity for discovering the unknown etiologies, but this depends on efficient powerful analytical methods. We built a compact database, ‘Rareservoir’, containing variant genotypes phenotypes 77,539 participants sequenced by 100,000 Genomes Project. then used Bayesian association method BeviMed to infer associations between genes each 269 disease classes assigned clinicians participants. identified 241 known 19 previously unidentified associations. validated with ERG , PMEPA1 GPR156 searching pedigrees in other using bioinformatic experimental approaches. evidence that (1) loss-of-function variants Erythroblast Transformation Specific (ETS)-family transcription factor encoding gene lead primary lymphoedema, (2) truncating last exon transforming growth factor-β regulator result Loeys–Dietz syndrome (3) give rise recessive congenital hearing impairment. Rareservoir provides lightweight, flexible portable system synthesizing phenotypic data required study tens thousands

Language: Английский

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The role of structural dynamics in GPCR‐mediated signaling

FEBS Journal, Journal Year: 2021, Volume and Issue: 288(8), P. 2461 - 2489

Published: April 1, 2021

G protein‐coupled receptors (GPCRs) play critical roles in the regulation of human physiology response to a wide array different extracellular stimuli and thus represent one largest groups therapeutic drug targets. Recent advances structural characterization GPCRs conformations complex with proteins arrestins have provided important insights into mechanism function GPCRs. However, order truly understand molecular basis functional versatility GPCRs, snapshots obtained by X‐ray crystallography or cryo‐EM need be complimented information about conformational dynamics their signaling complexes. In last decade, combination biophysical approaches computational studies has been utilized examine motions transducer complexes how they are regulated ligands efficacy bias. These revealed that highly dynamic allosteric can sample multiple states. Ligands distinct profiles not only impact landscape but also receptor‐engaged arrestins. The ligand‐dependent bias sampling states underlying principles behind behavior

Language: Английский

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Molecular mechanisms of metabotropic GABA _B receptor function

Science Advances, Journal Year: 2021, Volume and Issue: 7(22)

Published: May 28, 2021

This review outlines the current understanding of structure and activation mechanism metabotropic GABA B receptors.

Language: Английский

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Amino acid sensor conserved from bacteria to humans

Proceedings of the National Academy of Sciences, Journal Year: 2022, Volume and Issue: 119(10)

Published: March 1, 2022

SignificanceAmino acids are the building blocks of life and important signaling molecules. Despite their common structure, no universal mechanism for amino acid recognition by cellular receptors is currently known. We discovered a simple motif, which binds in various receptor proteins from all major life-forms. In humans, this motif found subunits calcium channels that implicated pain neurodevelopmental disorders. Our findings suggest γ-aminobutyric acid-derived drugs bind to same human natural ligands bacterial receptors, thus enabling future improvement drugs.

Language: Английский

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Structure, function and drug discovery of GPCR signaling

Molecular Biomedicine, Journal Year: 2023, Volume and Issue: 4(1)

Published: Dec. 4, 2023

G protein-coupled receptors (GPCRs) are versatile and vital proteins involved in a wide array of physiological processes responses, such as sensory perception (e.g., vision, taste, smell), immune response, hormone regulation, neurotransmission. Their diverse essential roles the body make them significant focus for pharmaceutical research drug development. Currently, approximately 35% marketed drugs directly target GPCRs, underscoring their prominence therapeutic targets. Recent advances structural biology have substantially deepened our understanding GPCR activation mechanisms interactions with G-protein arrestin signaling pathways. This review offers an in-depth exploration both traditional recent methods structure analysis. It presents structure-based insights into ligand recognition receptor delves deeper canonical noncanonical pathways downstream GPCRs. Furthermore, it highlights advancements GPCR-related discovery Particular emphasis is placed on selective drugs, allosteric biased signaling, polyphamarcology, antibody drugs. Our goal to provide researchers thorough updated determination, pathway investigation, foundation aims propel forward-thinking approaches that drawing upon latest selectivity, activation, mechanisms.

Language: Английский

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Concerted conformational changes control metabotropic glutamate receptor activity

Science Advances, Journal Year: 2023, Volume and Issue: 9(22)

Published: June 2, 2023

Allosteric modulators bear great potential to fine-tune neurotransmitter action. Promising targets are metabotropic glutamate (mGlu) receptors, which associated with numerous brain diseases. Orthosteric and allosteric ligands act in synergy control the activity of these multidomain dimeric GPCRs. Here, we analyzed effect such molecules on concerted conformational changes full-length mGlu2 at single-molecule level. We first established FRET sensors through genetic code expansion combined click chemistry monitor live cells. then used show that orthosteric agonist binding leads stabilization most domains their closed state, while reorientation dimer into active state remains partial. modulators, interacting transmembrane domain, required stabilize fully reoriented dimer. These results illustrate how within proteins activity, modulated by ligands.

Language: Английский

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G protein-coupled receptor-effector macromolecular membrane assemblies (GEMMAs)

Pharmacology & Therapeutics, Journal Year: 2021, Volume and Issue: 231, P. 107977 - 107977

Published: Sept. 1, 2021

G protein-coupled receptors (GPCRs) are the largest group of involved in cellular signaling across plasma membrane and a major class drug targets. The canonical model for GPCR involves three components — GPCR, heterotrimeric protein proximal effector that have been generally thought to be freely mobile molecules able interact by 'collision coupling'. Here, we synthesize evidence supports existence GPCR–effector macromolecular assemblies (GEMMAs) comprised specific GPCRs, proteins, other associated transmembrane proteins pre-assembled prior receptor activation agonists, which then leads subsequent rearrangement GEMMA components. concept offers an alternative complementary collision-coupling model, allowing more efficient interactions between components, as well integration oligomerization with orphan receptors, truncated GPCRs membrane-localized GPCR-associated proteins. Collision-coupling mechanisms not exclusive likely both operate cell, providing spectrum modalities explains differential properties multitude their different environments. explore unique pharmacological characteristics individual GEMMAs, could provide new opportunities therapeutically modulate signaling.

Language: Английский

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Structural insights into the activation of human calcium-sensing receptor

eLife, Journal Year: 2021, Volume and Issue: 10

Published: Sept. 1, 2021

Human calcium-sensing receptor (CaSR) is a G-protein-coupled that maintains Ca 2+ homeostasis in serum. Here, we present the cryo-electron microscopy structures of CaSR inactive and agonist+PAM bound states. Complemented with previously reported CaSR, show addition to full active states, there are multiple intermediate states during activation CaSR. We used negative allosteric nanobody stabilize fully state found new binding site for ion acts as composite agonist L-amino acid closure Venus flytraps. Our data leads compaction dimer, proximity cysteine-rich domains, large-scale transitions seven-transmembrane inter- intrasubunit conformational changes domains accommodate downstream transducers. results reveal structural basis mechanisms clarify mode action ions leading receptor.

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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