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Title: Molecular mechanism of ATP binding and ion channel activation in P2X receptors

Abstract

P2X receptors are trimeric ATP-activated ion channels permeable to Na{sup +}, K{sup +} and Ca{sup 2+}. The seven P2X receptor subtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses. Despite the importance of P2X receptors in cellular physiology, the three-dimensional composition of the ATP-binding site, the structural mechanism of ATP-dependent ion channel gating and the architecture of the open ion channel pore are unknown. Here we report the crystal structure of the zebrafish P2X4 receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals a previously unseen ATP-binding motif and an open ion channel pore. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body {beta}-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices. The structural delineation of the ATP-binding site and the ion channel pore, together with the conformational changes associated with ion channel gating, will stimulate development of new pharmacological agents.

Authors:
;  [1]
  1. (Oregon HSU)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGNOTHERNIHHHMI
OSTI Identifier:
1045043
Resource Type:
Journal Article
Journal Name:
Nature
Additional Journal Information:
Journal Volume: 485; Journal Issue: 05, 2012
Country of Publication:
United States
Language:
ENGLISH
Subject:
37 INORGANIC, ORGANIC, PHYSICAL AND ANALYTICAL CHEMISTRY; ARCHITECTURE; BIOCHEMISTRY; BIOLOGY; CLOSURES; CONFORMATIONAL CHANGES; CONTRACTION; CRYSTAL STRUCTURE; MODULATION; OPENINGS; PHYSIOLOGY; REGULATIONS; SECRETION

Citation Formats

Hattori, Motoyuki, and Gouaux, Eric. Molecular mechanism of ATP binding and ion channel activation in P2X receptors. United States: N. p., 2012. Web. doi:10.1038/nature11010.
Hattori, Motoyuki, & Gouaux, Eric. Molecular mechanism of ATP binding and ion channel activation in P2X receptors. United States. doi:10.1038/nature11010.
Hattori, Motoyuki, and Gouaux, Eric. Wed . "Molecular mechanism of ATP binding and ion channel activation in P2X receptors". United States. doi:10.1038/nature11010.
@article{osti_1045043,
title = {Molecular mechanism of ATP binding and ion channel activation in P2X receptors},
author = {Hattori, Motoyuki and Gouaux, Eric},
abstractNote = {P2X receptors are trimeric ATP-activated ion channels permeable to Na{sup +}, K{sup +} and Ca{sup 2+}. The seven P2X receptor subtypes are implicated in physiological processes that include modulation of synaptic transmission, contraction of smooth muscle, secretion of chemical transmitters and regulation of immune responses. Despite the importance of P2X receptors in cellular physiology, the three-dimensional composition of the ATP-binding site, the structural mechanism of ATP-dependent ion channel gating and the architecture of the open ion channel pore are unknown. Here we report the crystal structure of the zebrafish P2X4 receptor in complex with ATP and a new structure of the apo receptor. The agonist-bound structure reveals a previously unseen ATP-binding motif and an open ion channel pore. ATP binding induces cleft closure of the nucleotide-binding pocket, flexing of the lower body {beta}-sheet and a radial expansion of the extracellular vestibule. The structural widening of the extracellular vestibule is directly coupled to the opening of the ion channel pore by way of an iris-like expansion of the transmembrane helices. The structural delineation of the ATP-binding site and the ion channel pore, together with the conformational changes associated with ion channel gating, will stimulate development of new pharmacological agents.},
doi = {10.1038/nature11010},
journal = {Nature},
number = 05, 2012,
volume = 485,
place = {United States},
year = {2012},
month = {10}
}