Numerous physiological functions rely on distinguishing temperature through temperature-sensitive transient receptor potential channels (thermo-TRPs). Although the function of thermo-TRPs has been studied extensively, structural determination of their heat- and cold-activated states has remained a challenge. Here, we present cryo-EM structures of the nanodisc-reconstituted wild-type mouse TRPV3 in three distinct conformations: closed, heat-activated sensitized and open states. The heat-induced transformations of TRPV3 are accompanied by changes in the secondary structure of the S2-S3 linker and the N and C termini and represent a conformational wave that links these parts of the protein to a lipid occupying the vanilloid binding site. State-dependent differences in the behavior of bound lipids suggest their active role in thermo-TRP temperature-dependent gating. Our structural data, supported by physiological recordings and molecular dynamics simulations, provide an insight for understanding the molecular mechanism of temperature sensing.

许多生理功能依赖于通过温度敏感的瞬时受体电位通道 (thermo-TRP) 来区分温度。尽管热 TRP 的功能已得到广泛研究，但其热激活和冷激活状态的结构确定仍然是一个挑战。在这里，我们展示了三种不同构象的纳米圆盘重组野生型小鼠 TRPV3 的冷冻电镜结构：闭合状态、热激活致敏状态和开放状态。TRPV3 的热诱导转化伴随着 S2-S3 接头的二级结构以及 N 和 C 末端的变化，并代表将蛋白质的这些部分连接到占据香草素结合位点的脂质的构象波。结合脂质行为的状态依赖性差异表明它们在 thermo-TRP 温度依赖性门控中的积极作用。我们的结构数据在生理记录和分子动力学模拟的支持下，为理解温度传感的分子机制提供了见解。