Structure of the human M2 muscarinic acetylcholine receptor bound to an antagonist

By K. Haga, A. Kruse, H. Asada, Takami Yurugi-Kobayashi, M. Shiroishi, William I. Weis, T. Okada, Brian K. Kobilka, T. Haga, Takuya Kobayashi. Nature, 2012

821 citations recorded by the source corpus.

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.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Radiology, Nuclear Medicine and Imaging

View Paper: https://www.semanticscholar.org/paper/c6c89ad2640e960fea2a3c6f0882f5a5bf4d161e

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Citations in the corpus

Ligand–receptor interaction platforms and their applications for drug discovery (2012, background): “These include rhodopsin [124], b2-adrenergic receptor [125], b1-adrenergic receptor [126], adenosine A2A receptor [127], CXCR4 chemokine receptor [128], dopamine D3 receptor [129], histamine H1 receptor [130], sphingosine 1-phosphate S1P1 receptor [131], muscarinic M3 acetylcholine receptor [132], m”
Structure-Function of the G-protein-Coupled Receptor Superfamily (2012, background): “48 side chain in most GPCR structures that have been solved, this passage is more open in the muscarinic M2 and M3 receptors (30, 31).”
Multiple conformational states in retrospective virtual screening – homology models vs. crystal structures: beta-2 adrenergic receptor case study (2015, neutral): “M2R 3UON [30] 3.”
Structure-based drug screening for G-protein-coupled receptors. (2012, background): “Since the initial crystal structures of the β2AR[11] and the β1AR[12], the number of published GPCRs which have yielded to crystallography has grown to ten and includes the adenosine A2A receptor[13], the D3 dopamine receptor[14], the CXCR4 receptor [15], the histamine H1 receptor, [16], the sphingo”
Structure of the δ-opioid receptor bound to naltrindole (2012, neutral): “OR with the M 2 muscarinic receptor 16 (Fig.”
GPCR Network: a large-scale collaboration on GPCR structure and function (2012, background): “31) , rat muscarinic acetylcholine receptor M 3 (REF.”
Generic GPCR Residue Numbers - Aligning Topology Maps Minding The Gaps (2014, background): “The aminergic muscarinic acetylcholine M 2 and M 3 receptor crystal structures [66,67] are not constricted in TM4, and the structurally equivalent position of the conserved tryptophan is 4.57.”