Transient receptor potential vanilloid subfamily member 3 (TRPV3) is a temperature-sensitive cation channel. Previous cryo-EM analyses of TRPV3 in detergent micelles or amphipol proposed that the lower gate opens by α-to-π helical transitions of the nearby S6 helix. However, it remains unclear how physiological lipids are involved in the TRPV3 activation. Here we determined the apo state structure of mouse (Mus musculus) TRPV3 in a lipid nanodisc at 3.3 Å resolution. The structure revealed that lipids bound to the pore domain stabilize the selectivity filter in the narrow state, suggesting that the selectivity filter of TRPV3 affects cation permeation. When the lower gate is closed in nanodisc-reconstituted TRPV3, the S6 helix adopts the π-helical conformation without agonist- or heat-sensitization, potentially stabilized by putative intra-subunit hydrogen bonds and lipid binding. Our findings provide insights into the lipid-associated gating mechanism of TRPV3.

瞬时受体电位香草素亚家族成员 3 (TRPV3) 是一种温度敏感的阳离子通道。先前对洗涤剂胶束或两性酚中 TRPV3 的低温 EM 分析表明，下门通过附近 S6 螺旋的 α 到 π 螺旋跃迁打开。然而，尚不清楚生理脂质如何参与 TRPV3 激活。在这里，我们确定了小鼠 ( Mus musculus ) 的 apo 状态结构) 脂质纳米盘中的 TRPV3，分辨率为 3.3 Å。该结构表明，与孔域结合的脂质将选择性过滤器稳定在狭窄状态，表明 TRPV3 的选择性过滤器影响阳离子渗透。当在纳米圆盘重组的 TRPV3 中关闭下门时，S6 螺旋采用 π 螺旋构象，没有激动剂或热敏化，可能通过假定的亚基内氢键和脂质结合来稳定。我们的研究结果提供了对 TRPV3 脂质相关门控机制的见解。