Activation and dynamic network of the M2 muscarinic receptor

作者：Miao Yinglong^*; Nichols Sara E; Gasper Paul M; Metzger Vincent T; McCammon J Andrew

来源：Proceedings of the National Academy of Sciences, 2013, 110(27): 10982-10987.

DOI：10.1073/pnas.1309755110

• enhanced sampling
• GPCR signaling
• allosteric network
• cross-correlations
• drug design

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 similar to 6-angstrom outward tilting of the cytoplasmic end of transmembrane alpha-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.

• 出版日期2013-7-2