ArticleNature2012
Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist.
Article in Nature, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 329 papers.
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Who cites it
329 citing papers in PubMed, 790 citations in OpenAlex.
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- Adiabatic-Bias Molecular Dynamics Simulations Reveal the Impact of Mutations on Muscarinic Antagonist Unbinding Kinetics.Journal of chemical information and modeling · 2025Article
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- 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
- A New Era of Muscarinic Acetylcholine Receptor Modulators in Neurological Diseases, Cancer and Drug Abuse.Pharmaceuticals (Basel, Switzerland) · 2025Review
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269 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 5 institutions in 2 countries.
Funding
Abstract
The parasympathetic branch of the autonomic nervous system regulates the activity of multiple organ systems. Muscarinic receptors are G-protein-coupled receptors that mediate the response to acetylcholine released from parasympathetic nerves. Their role in the unconscious regulation of organ and central nervous system function makes them potential therapeutic targets for a broad spectrum of diseases. The M2 muscarinic acetylcholine receptor (M2 receptor) is essential for the physiological control of cardiovascular function through activation of G-protein-coupled inwardly rectifying potassium channels, and is of particular interest because of its extensive pharmacological characterization with both orthosteric and allosteric ligands. Here we report the structure of the antagonist-bound human M2 receptor, the first human acetylcholine receptor to be characterized structurally, to our knowledge. The antagonist 3-quinuclidinyl-benzilate binds in the middle of a long aqueous channel extending approximately two-thirds through the membrane. The orthosteric binding pocket is formed by amino acids that are identical in all five muscarinic receptor subtypes, and shares structural homology with other functionally unrelated acetylcholine binding proteins from different species. A layer of tyrosine residues forms an aromatic cap restricting dissociation of the bound ligand. A binding site for allosteric ligands has been mapped to residues at the entrance to the binding pocket near this aromatic cap. The structure of the M2 receptor provides insights into the challenges of developing subtype-selective ligands for muscarinic receptors and their propensity for allosteric regulation.
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Registered trials
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.