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Nat Chem Biol. 2018 Dec;14(12):1150-1158. doi: 10.1038/s41589-018-0152-y. Epub 2018 Nov 12.

Structural insights into the subtype-selective antagonist binding to the M2 muscarinic receptor.

Author information

1
Department of Cell Biology and Medical Chemistry, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, Japan. r.suno@mfour.med.kyoto-u.ac.jp.
2
Department of Molecular Imaging and Therapy, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
3
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, CA, USA.
4
Graduate School of Science and Molecular Chirality Research Center, Chiba University, Inage, Chiba, Japan.
5
RIKEN, SPring-8 Center, Hyogo, Japan.
6
Japan Science and Technology Agency, Precursory Research for Embryonic Science and Technology (PRESTO), Kawaguchi, Saitama, Japan.
7
Department of Cell Biology and Medical Chemistry, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, Japan.
8
Institute of Advanced Energy and Graduate School of Energy Science, Kyoto University, Uji, Kyoto, Japan.
9
Japan Science and Technology Agency, Research Acceleration Program, Membrane Protein Crystallography Project, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, Japan.
10
Department of Cell Biology and Medical Chemistry, Graduate School of Medicine, Kyoto University, Konoe-cho, Yoshida, Sakyo-ku, Kyoto, Japan. kobayashi.takuya.4r@kyoto-u.ac.jp.
11
Japan Science and Technology Agency (JST) and Japan Agency for Medical Research and Development (AMED), Core Research for Evolutional Science and Technology (CREST), Konoe-cho, Yoshida, Sakyo-ku, Kyoto, Japan. kobayashi.takuya.4r@kyoto-u.ac.jp.

Abstract

Human muscarinic receptor M2 is one of the five subtypes of muscarinic receptors belonging to the family of G-protein-coupled receptors. Muscarinic receptors are targets for multiple neurodegenerative diseases. The challenge has been designing subtype-selective ligands against one of the five muscarinic receptors. We report high-resolution structures of a thermostabilized mutant M2 receptor bound to a subtype-selective antagonist AF-DX 384 and a nonselective antagonist NMS. The thermostabilizing mutation S110R in M2 was predicted using a theoretical strategy previously developed in our group. Comparison of the crystal structures and pharmacological properties of the M2 receptor shows that the Arg in the S110R mutant mimics the stabilizing role of the sodium cation, which is known to allosterically stabilize inactive state(s) of class A GPCRs. Molecular dynamics simulations reveal that tightening of the ligand-residue contacts in M2 receptors compared to M3 receptors leads to subtype selectivity of AF-DX 384.

PMID:
30420692
PMCID:
PMC6462224
DOI:
10.1038/s41589-018-0152-y
[Indexed for MEDLINE]
Free PMC Article

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