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

Publication Type:

Journal Article


Nat Struct Mol Biol, Volume 25, Issue 3, p.252-260 (2018)


<p>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.</p>

X-ray structures of Cs+, Ba2+ and Gd3+-bound TRPV4 have been deposited in the wwPDB with accession codes PDB 6C8F, PDB 6C8G and PDB 6C8H, respectively.