The TRPV3 channel plays vital roles in skin physiology. Dysfunction of TRPV3 causes skin diseases, including Olmsted syndrome. However, the lack of potent and selective inhibitors impedes the validation of TRPV3 as a therapeutic target. In this study, we identified Trpvicin as a potent and subtype-selective inhibitor of TRPV3. Trpvicin exhibits pharmacological potential in the inhibition of itch and hair loss in mouse models. Cryogenic electron microscopy structures of TRPV3 and the pathogenic G573S mutant complexed with Trpvicin reveal detailed ligand-binding sites, suggesting that Trpvicin inhibits the TRPV3 channel by stabilizing it in a closed state. Our G573S mutant structures demonstrate that the mutation causes a dilated pore, generating constitutive opening activity. Trpvicin accesses additional binding sites inside the central cavity of the G573S mutant to remodel the channel symmetry and block the channel. Together, our results provide mechanistic insights into the inhibition of TRPV3 by Trpvicin and support TRPV3-related drug development.

TRPV3 通道在皮肤生理学中起着至关重要的作用。TRPV3 的功能障碍会导致皮肤病，包括奥姆斯特德综合征。然而，缺乏强效和选择性抑制剂阻碍了 TRPV3 作为治疗靶点的验证。在这项研究中，我们将 Trpvicin 鉴定为一种有效的亚型选择性 TRPV3 抑制剂。在小鼠模型中，Trpvicin 在抑制瘙痒和脱发方面具有药理学潜力。TRPV3 的低温电子显微镜结构和与 Trpvicin 复合的致病性 G573S 突变体揭示了详细的配体结合位点，表明 Trpvicin 通过将其稳定在关闭状态来抑制 TRPV3 通道。我们的 G573S 突变体结构表明该突变会导致毛孔扩张，从而产生组成型开放活性。Trpvicin 访问 G573S 突变体中央腔内的其他结合位点，以重塑通道对称性并阻断通道。总之，我们的结果提供了对 Trpvicin 抑制 TRPV3 的机制见解，并支持 TRPV3 相关药物的开发。