TRPV3, a representative of the vanilloid subfamily of TRP channels, is predominantly expressed in skin keratinocytes and has been implicated in cutaneous sensation and associated with numerous skin pathologies and cancers. TRPV3 is inhibited by the natural coumarin derivative osthole, an active ingredient of Cnidium monnieri, which has been used in traditional Chinese medicine for the treatment of a variety of human diseases. However, the structural basis of channel inhibition by osthole has remained elusive. Here we present cryo-EM structures of TRPV3 in complex with osthole, revealing two types of osthole binding sites in the transmembrane region of TRPV3 that coincide with the binding sites of agonist 2-APB. Osthole binding converts the channel pore into a previously unidentified conformation with a widely open selectivity filter and closed intracellular gate. Our structures provide insight into competitive inhibition of TRPV3 by osthole and can serve as a template for the design of osthole chemistry-inspired drugs targeting TRPV3-associated diseases.

中文翻译：

---

植物源香豆素蛇床子素抑制 TRPV3 通道的结构机制

TRPV3 是 TRP 通道香草酸亚家族的代表，主要在皮肤角质形成细胞中表达，与皮肤感觉有关，并与多种皮肤病理和癌症相关。TRPV3 受到天然香豆素衍生物蛇床子素的抑制，蛇床子素是蛇床子的活性成分，在中药中用于治疗多种人类疾病。然而，蛇床子素抑制通道的结构基础仍然难以捉摸。在这里，我们展示了 TRPV3 与蛇床子素复合物的冷冻电镜结构，揭示了 TRPV3 跨膜区域中两种类型的蛇床子素结合位点，它们与激动剂 2-APB 的结合位点一致。蛇床子素结合将通道孔转化为先前未识别的构象，具有广泛开放的选择性过滤器和封闭的细胞内门。我们的结构提供了对蛇床子素对 TRPV3 的竞争性抑制的深入了解，并且可以作为设计针对 TRPV3 相关疾病的蛇床子素化学启发药物的模板。