title: Activation and dynamic network of the M2 muscarinic receptor.
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.
authors.affiliation: Howard Hughes Medical Institute, University of California at San Diego, La Jolla, CA 92093, USA. yimiao@ucsd.edu
authors.forename: Yinglong
authors.initials: Y
authors.lastname: Miao
authors.forename: Sara E
authors.initials: SE
authors.lastname: Nichols
authors.forename: Paul M
authors.initials: PM
authors.lastname: Gasper
authors.forename: Vincent T
authors.initials: VT
authors.lastname: Metzger
authors.forename: J Andrew
authors.initials: JA
authors.lastname: McCammon
mesh_terms: D001665:Binding Sites; D006801:Humans; D006860:Hydrogen Bonding; D008024:Ligands; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D043585:Receptor, Muscarinic M2 / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D008024:Ligands; D043585:Receptor, Muscarinic M2
keywords: GPCR signaling; allosteric network; cross-correlations; drug design; enhanced sampling