Abstract

The transient receptor potential vanilloid 4 (TRPV4) channel is a polymodal receptor that is activated by warm temperature, osmolarity changes, and many ligands1. Like other members in the TRPV family, TRPV4 is critically involved in a plethora of physiological processes like temperature sensation, osmoregulation, and mechanotransduction. Importantly, TRPV4 has the largest number of mutations associated with human diseases2 among the TRPV channels. Therefore, TRPV4 has been heavily targeted in drug developments3 against diseases like chronic cough (NCT03372603) and heart failure (NCT02497937 and NCT02119260). Despite the high-resolution structures of all other members in the TRPV family in mammals have been resolved4, to date the only peer-reviewed and published structure of TRPV4 is from Xenopus tropicalis (xTRPV4), which is in the apo state with an S4-S5 linker distinct from most of TRPV channels5, offering limited information regarding the ligand gating mechanism of this channel.To understand how the TRPV4 channel is activated and inhibited by ligands and to facilitate drug development targeting this channel in the future, we have resolved the structures of mouse TRPV4 in the apo state (mTRPV4apo, 3.6 Å), in complex with the agonist GSK1016790A (GSK101) (mTRPV4GSK101, 3.6 Å), in complex with both GSK101 and ruthenium red (RR) (mTRPV4GSK101_RR, 3.7 Å) and in complex with Agonist-1 and RR (mTRPV4Agonist1_RR, 3.9 Å) states by cryo-electron microscopy (cryo-EM) .

原文链接：https://www.nature.com/articles/s41421-023-00579-3