The transient receptor potential vanilloid 5 (TRPV5) channel is a member of the transient receptor potential (TRP) channel family, which is highly selective for Ca²⁺, that is present primarily at the apical membrane of distal tubule epithelial cells in the kidney and plays a key role in Ca²⁺ reabsorption. Here we present the structure of the full-length rabbit TRPV5 channel as determined using cryo-EM in complex with its inhibitor econazole. This structure reveals that econazole resides in a hydrophobic pocket analogous to that occupied by phosphatidylinositides and vanilloids in TRPV1, thus suggesting conserved mechanisms for ligand recognition and lipid binding among TRPV channels. The econazole-bound TRPV5 structure adopts a closed conformation with a distinct lower gate that occludes Ca²⁺ permeation through the channel. Structural comparisons between TRPV5 and other TRPV channels, complemented with molecular dynamics (MD) simulations of the econazole-bound TRPV5 structure, allowed us to gain mechanistic insight into TRPV5 channel inhibition by small molecules.

瞬时受体电位香草酸 5 (TRPV5) 通道是瞬时受体电位 (TRP) 通道家族的成员，它对 Ca ²⁺具有高度选择性，主要存在于肾脏远端小管上皮细胞的顶膜和在 Ca ²⁺中起关键作用重吸收。在这里，我们展示了全长兔 TRPV5 通道的结构，该通道使用低温 EM 与其抑制剂益康唑复合测定。这种结构表明益康唑位于一个疏水口袋中，类似于 TRPV1 中磷脂酰肌醇和香草醛所占据的口袋，因此表明了 TRPV 通道之间配体识别和脂质结合的保守机制。与益康唑结合的 TRPV5 结构采用封闭构象，具有明显的下门，可阻挡 Ca ²⁺通过通道的渗透。TRPV5 和其他 TRPV 通道之间的结构比较，辅以益康唑结合的 TRPV5 结构的分子动力学 (MD) 模拟，使我们能够从机理上了解小分子对 TRPV5 通道的抑制作用。