Structure and gating mechanism of the transient receptor potential channel TRPV3.

Abstract

The transient receptor potential (TRP) channel TRPV3 plays a crucial role in skin physiology and pathophysiology. Mutations in TRPV3 are associated with various skin diseases, including Olmsted syndrome, atopic dermatitis and rosacea. Here we present cryo-EM structures of full length mouse TRPV3 in the closed and agonist-bound open states. The agonist binds three allosteric sites distal to the pore. Channel opening is accompanied by conformational changes in both the outer pore and the intracellular gate. The gate is formed by the pore-lining S6 helices that undergo local α-to-π helical transitions, elongate, rotate, and splay apart in the open state. In the closed state, the shorter S6 segments are entirely α-helical, expose their non-polar surfaces to the pore, and hydrophobically seal the ion permeation pathway. These findings further illuminate TRP channel activation and can aid in design of drugs for the treatment of inflammatory skin conditions, itch and pain.