TY - JOUR
T1 - Crystal structure of the ATP-gated P2X4 ion channel in the closed state
AU - Kawate, Toshimitsu
AU - Michel, Jennifer Carlisle
AU - Birdsong, William T.
AU - Gouaux, Eric
N1 - Funding Information:
Acknowledgements We thank the personnel at beamlines 5.0.2, 8.2.1 and 8.2.2 of the Advanced Light Source and at beamline 24-ID-E of the Advanced Photon Source. We also thank M. Voigt for zebrafish P2X receptor DNA, T. Homrichhausen for help with cloning and FSEC screening, J. Berriman for help with electron microscopy, L. Vaskalis for assistance with illustrations, and Gouaux laboratory members for discussions. This work was supported by the National Institutes of Health (NIH) and the American Asthma Foundation. E.G. is an investigator with the Howard Hughes Medical Institute.
PY - 2009/7/30
Y1 - 2009/7/30
N2 - P2X receptors are cation-selective ion channels gated by extracellular ATP, and are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is at present no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X 4 receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in Β-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the gate is defined by an 8 slab of protein. We define the location of three non-canonical, intersubunit ATP-binding sites, and suggest that ATP binding promotes subunit rearrangement and ion channel opening.
AB - P2X receptors are cation-selective ion channels gated by extracellular ATP, and are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is at present no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X 4 receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit-subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in Β-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the gate is defined by an 8 slab of protein. We define the location of three non-canonical, intersubunit ATP-binding sites, and suggest that ATP binding promotes subunit rearrangement and ion channel opening.
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U2 - 10.1038/nature08198
DO - 10.1038/nature08198
M3 - Article
C2 - 19641588
AN - SCOPUS:67949117176
SN - 0028-0836
VL - 460
SP - 592
EP - 598
JO - Nature
JF - Nature
IS - 7255
ER -