ArticleProceedings of the National Academy of Sciences of the United States of America2013
Activation and dynamic network of the M2 muscarinic receptor.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 118 papers.
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Who cites it
118 citing papers in PubMed, 226 citations in OpenAlex.
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- Molecular basis of ligand binding and receptor activation at the human ANature communications · 2025Article
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- The Cardiomyocyte in Cirrhosis: Pathogenic Mechanisms Underlying Cirrhotic Cardiomyopathy.Reviews in cardiovascular medicine · 2024Review
- A non-canonical mechanism of GPCR activation.Nature communications · 2024Article
- Mechanical stress and anionic lipids synergistically stabilize an atypical structure of the angiotensin II type 1 receptor (AT1).PLoS computational biology · 2024Article
- Single-molecule FRET probes allosteric effects on protein-translocating pore loops of a AAA+ machine.Biophysical journal · 2024Article
- Mechanistic Insights into Peptide Binding and Deactivation of an Adhesion G Protein-Coupled Receptor.Molecules (Basel, Switzerland) · 2023Article
- Connected Component Analysis of Dynamical Perturbation Contact Networks.The journal of physical chemistry. B · 2023Article
- Structural basis of efficacy-driven ligand selectivity at GPCRs.Nature chemical biology · 2023Article
- Computational design of dynamic receptor-peptide signaling complexes applied to chemotaxis.Nature communications · 2023Article
- The full activation mechanism of the adenosine AProceedings of the National Academy of Sciences of the United States of America · 2022Article
- In Silico Study of Allosteric Communication Networks in GPCR Signaling Bias.International journal of molecular sciences · 2022Review
- GLOW: A Workflow Integrating Gaussian-Accelerated Molecular Dynamics and Deep Learning for Free Energy Profiling.Journal of chemical theory and computation · 2022Article
- Structure of the stress-related LHCSR1 complex determined by an integrated computational strategy.Communications biology · 2022Article
- Unique features of different classes of G-protein-coupled receptors revealed from sequence coevolutionary and structural analysis.Proteins · 2022Article
58 more citing papers are in PubMed but not listed here.
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Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
G-protein-coupled receptors (GPCRs) mediate cellular responses to various hormones and neurotransmitters and are important targets for treating a wide spectrum of diseases. Although significant advances have been made in structural studies of GPCRs, details of their activation mechanism remain unclear. The X-ray crystal structure of the M2 muscarinic receptor, a key GPCR that regulates human heart rate and contractile forces of cardiomyocytes, was determined recently in an inactive antagonist-bound state. Here, activation of the M2 receptor is directly observed via accelerated molecular dynamics simulation, in contrast to previous microsecond-timescale conventional molecular dynamics simulations in which the receptor remained inactive. Receptor activation is characterized by formation of a Tyr206(5.58)-Tyr440(7.53) hydrogen bond and ∼6-Å outward tilting of the cytoplasmic end of transmembrane α-helix 6, preceded by relocation of Trp400(6.48) toward Phe195(5.47) and Val199(5.51) and flipping of Tyr430(7.43) away from the ligand-binding cavity. Network analysis reveals that communication in the intracellular domains is greatly weakened during activation of the receptor. Together with the finding that residue motions in the ligand-binding and G-protein-coupling sites of the apo receptor are correlated, this result highlights a dynamic network for allosteric regulation of the M2 receptor activation.
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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.