ArticleNature communications2023
Structural and dynamic insights into supra-physiological activation and allosteric modulation of a muscarinic acetylcholine receptor.
Article in Nature communications, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 45 citations in OpenAlex.
- An Improved Cysteine-Based Labeling Strategy for GPCR Structural Dynamics Studies.Chemistry (Weinheim an der Bergstrasse, Germany) · 2026Article
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- The Role of Intrinsically Disordered Domains in Regulating G Protein-Coupled Receptor Signaling.Journal of the American Chemical Society · 2026Article
- The pathway-independent positive allosteric modulator C1 allows for the identification of active YCellular and molecular life sciences : CMLS · 2026Article
- Extracellular nanobody screening using conformationally stable GPCR variants.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- The role of intrinsically disordered domains in regulating G protein coupled receptor signaling.bioRxiv : the preprint server for biology · 2025Article
- Cryo-EM reveals an extrahelical allosteric binding site at the MNature communications · 2025Article
- Discovering Key Activation Hotspots in the MJournal of the American Chemical Society · 2025Article
- Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.Nature reviews. Drug discovery · 2025Review
- Visualizing agonist-induced M2 receptor activation regulated by aromatic ring dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Structural insights into physiological activation and antagonism of melanin-concentrating hormone receptor MCHR1.Cell discovery · 2024Article
- Positive allosteric modulation of a GPCR ternary complex.Science advances · 2024Article
- Article
- Multiple recent HCAR2 structures demonstrate a highly dynamic ligand binding and G protein activation mode.Nature communications · 2024Review
- The M3 Muscarinic Acetylcholine Receptor Can Signal through Multiple G Protein Families.Molecular pharmacology · 2024Article
- G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery.Signal transduction and targeted therapy · 2024Review
- Molecular mechanism of muscarinic acetylcholine receptor M3 interaction with Gq.Communications biology · 2024Article
- Unraveling allostery within the angiotensin II type 1 receptor for GαScience signaling · 2023Article
- Stabilization of pre-existing neurotensin receptor conformational states by β-arrestin-1 and the biased allosteric modulator ML314.Nature communications · 2023Article
- Article
Corrections and comments
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Authors and funding
13 authors at 8 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The M2 muscarinic receptor (M2R) is a prototypical G-protein-coupled receptor (GPCR) that serves as a model system for understanding GPCR regulation by both orthosteric and allosteric ligands. Here, we investigate the mechanisms governing M2R signaling versatility using cryo-electron microscopy (cryo-EM) and NMR spectroscopy, focusing on the physiological agonist acetylcholine and a supra-physiological agonist iperoxo, as well as a positive allosteric modulator LY2119620. These studies reveal that acetylcholine stabilizes a more heterogeneous M2R-G-protein complex than iperoxo, where two conformers with distinctive G-protein orientations were determined. We find that LY2119620 increases the affinity for both agonists, but differentially modulates agonists efficacy in G-protein and β-arrestin pathways. Structural and spectroscopic analysis suggest that LY211620 stabilizes distinct intracellular conformational ensembles from agonist-bound M2R, which may enhance β-arrestin recruitment while impairing G-protein activation. These results highlight the role of conformational dynamics in the complex signaling behavior of GPCRs, and could facilitate design of better drugs.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.