Du, Juan; Dong, Hao; Zhou, Huan-Xiang
Gating mechanism of a P2X4 receptor developed from normal mode analysis and molecular dynamics simulations
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 109:4140-4145, MAR 13 2012

P2X receptors are trimeric ATP-gated cation channels participating in diverse physiological processes. How ATP binding triggers channel opening remains unclear. Here the gating mechanism of a P2X receptor was studied by normal mode analysis and molecular dynamics (MD) simulations. Based on the resting-state crystal structure, a normal mode involving coupled motions of three beta-strands (beta 1, beta 13, and beta 14) at the trimeric interface of the ligand-binding ectodomain and the pore-lining helix (TM2) in the transmembrane domain (TMD) was identified. The resulting widening of the fenestrations above the TMD and opening of the transmembrane pore produce known signatures of channel activation. In MD simulations, ATP was initially placed in the putative binding pocket (defined by four charged residues located in beta 1, beta 13 and beta 14) in two opposite orientations, with the adenine either proximal or distal to the TMD. In the proximal orientation, the triphosphate group extends outward to draw in the four charged residues, leading to closure of beta 13/beta 14 toward beta 1. The adenine ring, wedged between beta 1 and beta 13, acts as a fulcrum for the beta 14 lever, turning a modest closure around the triphosphate group into significant opening of the pre-TM2 loop. The motions of these beta-strands are similar to those in the putative channel-activation normal mode. In the distal orientation, the ATP stabilizes the trimeric interface and the closure of the pre-TM2 loop, possibly representing desensitization. Our computational studies produced the first complete model, supported by experimental data, for how ATP binding triggers activation of a P2X receptor.

DOI:10.1073/pnas.1119546109

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