National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)
R01NS099341-01A1
米国
National Institutes of Health/National Cancer Institute (NIH/NCI)
P30 CA008748
米国
American Heart Association
17SDG33400229
米国
引用
ジャーナル: Nat Struct Mol Biol / 年: 2018 タイトル: Cryo-EM and X-ray structures of TRPV4 reveal insight into ion permeation and gating mechanisms. 著者: Zengqin Deng / Navid Paknejad / Grigory Maksaev / Monica Sala-Rabanal / Colin G Nichols / Richard K Hite / Peng Yuan / 要旨: 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 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.