TCB Publications - Abstract

TCB Publications - Abstract

Steven E. Mansoor, Wei Lü, Wout Oosterheert, Mrinal Shekhar, Emad Tajkhorshid, and Eric Gouaux. X-ray structures define human P2X3 receptor gating cycle and antagonist action. Nature, 538:66-71, 2016. (PMC: PMC5161641)

MANS2016A-ET P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems. Despite their central function in human physiology and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors. The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear. Here we report X-ray crystal structures of the human P2X$_{3}$ receptor in apo/resting, agonist- bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist- bound/closed states. The open state structure harbours an intracellular motif we term the 'cytoplasmic cap', which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress. The competitive antagonists TNP-ATP and A-317491 stabilize the apo/resting state and reveal the interactions responsible for competitive inhibition. These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents.

Download Full Text

The manuscripts available on our site are provided for your personal use only and may not be retransmitted or redistributed without written permissions from the paper's publisher and author. You may not upload any of this site's material to any public server, on-line service, network, or bulletin board without prior written permission from the publisher and author. You may not make copies for any commercial purpose. Reproduction or storage of materials retrieved from this web site is subject to the U.S. Copyright Act of 1976, Title 17 U.S.C.

Download full text: Supplemental Material (29.2MB) - Supplemental Movies, Request a Copy, Journal