Activation and Dynamic Network of the M2 Muscarinic Receptor
Dr. Yinglong Miao
McCammon Research Group
Howard Hughes Medical Institute
UC San Diego
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
Tyr2065.58-Tyr4407.53 hydrogen
bond and ~6 Å outward tilting of the cytoplasmic end of TM6, preceded
by relocation of
Trp4006.48 towards Phe1955.47 and Val1995.51
and flipping of Tyr4307.43 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.
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