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

Steven E. Mansoor, Wei Lü, Wout Oosterheert, Mrinal Shekhar, Emad Tajkhorshid, Eric Gouaux

Research output: Contribution to journalArticle

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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 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.

Original languageEnglish (US)
Pages (from-to)66-71
Number of pages6
JournalNature
Volume538
Issue number7623
DOIs
StatePublished - Sep 14 2016

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X-Rays
Receptors, Tumor Necrosis Factor, Member 25
Ions
Cardiovascular System
Ion Channels
Cations
Immune System
Phospholipids
Adenosine Triphosphate
Pharmacology
Water
Therapeutics
2',3'-O-(2,4,6-trinitro-cyclohexadienylidine)adenosine 5'-triphosphate

ASJC Scopus subject areas

  • Medicine(all)
  • General

Cite this

Mansoor, S. E., Lü, W., Oosterheert, W., Shekhar, M., Tajkhorshid, E., & Gouaux, E. (2016). X-ray structures define human P2X 3 receptor gating cycle and antagonist action. Nature, 538(7623), 66-71. https://doi.org/10.1038/nature19367

X-ray structures define human P2X 3 receptor gating cycle and antagonist action. / Mansoor, Steven E.; Lü, Wei; Oosterheert, Wout; Shekhar, Mrinal; Tajkhorshid, Emad; Gouaux, Eric.

In: Nature, Vol. 538, No. 7623, 14.09.2016, p. 66-71.

Research output: Contribution to journalArticle

Mansoor, SE, Lü, W, Oosterheert, W, Shekhar, M, Tajkhorshid, E & Gouaux, E 2016, 'X-ray structures define human P2X 3 receptor gating cycle and antagonist action', Nature, vol. 538, no. 7623, pp. 66-71. https://doi.org/10.1038/nature19367
Mansoor SE, Lü W, Oosterheert W, Shekhar M, Tajkhorshid E, Gouaux E. X-ray structures define human P2X 3 receptor gating cycle and antagonist action. Nature. 2016 Sep 14;538(7623):66-71. https://doi.org/10.1038/nature19367
Mansoor, Steven E. ; Lü, Wei ; Oosterheert, Wout ; Shekhar, Mrinal ; Tajkhorshid, Emad ; Gouaux, Eric. / X-ray structures define human P2X 3 receptor gating cycle and antagonist action. In: Nature. 2016 ; Vol. 538, No. 7623. pp. 66-71.
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