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Science. 2018 Jan 12;359(6372):228-232. doi: 10.1126/science.aar4510. Epub 2017 Dec 7.

Structure of the human TRPM4 ion channel in a lipid nanodisc.

Author information

1
Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143, USA.
2
Department of Molecular Biology and Genetics, University of Aarhus, 8000 Aarhus, Denmark.
3
Department of Physiology, University of California, San Francisco, CA 94143, USA.
4
Howard Hughes Medical Institute, University of California, San Francisco, CA 94143, USA.

Abstract

Transient receptor potential (TRP) melastatin 4 (TRPM4) is a widely expressed cation channel associated with a variety of cardiovascular disorders. TRPM4 is activated by increased intracellular calcium in a voltage-dependent manner but, unlike many other TRP channels, is permeable to monovalent cations only. Here we present two structures of full-length human TRPM4 embedded in lipid nanodiscs at ~3-angstrom resolution, as determined by single-particle cryo-electron microscopy. These structures, with and without calcium bound, reveal a general architecture for this major subfamily of TRP channels and a well-defined calcium-binding site within the intracellular side of the S1-S4 domain. The structures correspond to two distinct closed states. Calcium binding induces conformational changes that likely prime the channel for voltage-dependent opening.

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PMID:
29217581
PMCID:
PMC5898196
DOI:
10.1126/science.aar4510
[Indexed for MEDLINE]
Free PMC Article

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