Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 110, Issue 27, Pages 10982-10987Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1309755110
Keywords
enhanced sampling; GPCR signaling; allosteric network; cross-correlations; drug design
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Funding
- Extreme Science and Engineering Discovery Environment (XSEDE) [TG-MCA93S013]
- National Science Foundation [MCB1020765]
- National Institutes of Health [GM31749]
- Howard Hughes Medical Institute
- Center for Theoretical Biological Physics
- National Biomedical Computation Resource
- Direct For Biological Sciences
- Div Of Molecular and Cellular Bioscience [1020765] Funding Source: National Science Foundation
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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.
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