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Nat Struct Mol Biol. 2018 Mar;25(3):252-260. doi: 10.1038/s41594-018-0037-5. Epub 2018 Feb 26.

Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms.

Author information

1
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA.
2
Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, USA.
3
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
4
Structural Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA. hiter@mskcc.org.
5
Department of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA. yuanp@wustl.edu.
6
Center for the Investigation of Membrane Excitability Diseases, Washington University School of Medicine, St. Louis, MO, USA. yuanp@wustl.edu.

Abstract

The transient receptor potential (TRP) channel TRPV4 participates in multiple biological processes, and numerous TRPV4 mutations underlie several distinct and devastating diseases. Here we present the cryo-EM structure of Xenopus tropicalis TRPV4 at 3.8-Å resolution. The ion-conduction pore contains an intracellular gate formed by the inner helices, but lacks any extracellular gate in the selectivity filter, as observed in other TRPV channels. Anomalous X-ray diffraction analyses identify a single ion-binding site in the selectivity filter, thus explaining TRPV4 nonselectivity. Structural comparisons with other TRP channels and distantly related voltage-gated cation channels reveal an unprecedented, unique packing interface between the voltage-sensor-like domain and the pore domain, suggesting distinct gating mechanisms. Moreover, our structure begins to provide mechanistic insights to the large set of pathogenic mutations, offering potential opportunities for drug development.

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