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PMID: 27626375 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

X-ray structures define human P2X(3) receptor gating cycle and antagonist action.

Nature ·Vol. 538 ·No. 7623 ·2016-00-06 ·Pages 66-71

Mansoor SE, Lü W, Oosterheert W, Shekhar M, Tajkhorshid E, Gouaux E

Abstract

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 P2X3 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.

MeSH Terms
Apoproteins/agonists,antagonists & inhibitors,chemistry,metabolism Binding Sites/drug effects Binding, Competitive/drug effects Crystallization Crystallography, X-Ray Humans Ion Channel Gating/drug effects Ion Transport Ligands Models, Molecular Porosity Protein Conformation Purinergic Agonists/pharmacology Purinergic P2X Receptor Antagonists/pharmacology Receptors, Purinergic P2X3/chemistry,metabolism
Chemicals
Apoproteins Ligands Purinergic Agonists Purinergic P2X Receptor Antagonists Receptors, Purinergic P2X3
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Mansoor Steven E
Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. | Knight Cardiovascular Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
Lü Wei
Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
Oosterheert Wout
Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
Shekhar Mrinal
Department of Biochemistry, Center for Biophysics and Quantitative Biology, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Tajkhorshid Emad
Department of Biochemistry, Center for Biophysics and Quantitative Biology, and Beckman Institute for Advanced Science and Technology, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Gouaux Eric
Vollum Institute, Oregon Health &Science University, Portland, Oregon 97239, USA. | Howard Hughes Medical Institute, Oregon Health &Science University, Portland, Oregon 97239, USA.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature19367
Published
2016-00-06
Epub
2016-00-14
Pages
66-71
Language
English
Region
England
NLM ID
0410462
PMCID
PMC5161641
Subset
IM
Grants
NIGMS NIH HHS · F32 GM108391 · United States
NIGMS NIH HHS · R01 GM100400 · United States
NIGMS NIH HHS · U54 GM087519 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · P41 GM104601 · United States
External Links
PubMed source DOI: 10.1038/nature19367 PMC Full Text View journal details
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