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

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

SUBMITTER: Suno R 

PROVIDER: S-EPMC6462224 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature