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Department of Mathematics,
University of California San Diego

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Informal Seminar on Mathematics and Biochemistry-Biophysics

Yingiong Miao

HHMI, UCSD

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. While 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 (aMD) simulation, in contrast to previous microsecond-timescale conventional MD (cMD) 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 $\AA$ outward tilting of the cytoplasmic end of TM6, preceded by relocation of $Trp400^{6.48}$ towards $Phe195^{5.47}$ and $Val199^{5.51}$ and flipping of $Tyr430^{7.43}$ away from the ligandbinding 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 highlights a dynamic network for allosteric regulation of the M2 receptor activation.

Hosts: Li-Tien Cheng and Bo Li

May 16, 2013

2:00 PM

AP&M 5829

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