State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, 100871, Beijing, China.
Dizal Pharmaceutical Company, Jiangsu, China.
Cell Res. 2018 Jul;28(7):746-755. doi: 10.1038/s41422-018-0038-2. Epub 2018 Apr 26.
TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high-affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 Å resolution. We also present the structure of human TRPC3 at 4.4 Å resolution. These structures show two-layer architectures in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structures uncover the molecular architecture of TRPC channels and provide a structural basis for understanding the mechanism of these channels.
TRPC6 和 TRPC3 是受受体激活的非选择性阳离子通道，属于经典瞬时受体电位 (TRPC) 通道家族。它们被二酰基甘油激活，二酰基甘油是一种脂类第二信使。TRPC6 和 TRPC3 参与许多生理过程，并与人类遗传疾病有关。在这里，我们通过单颗粒冷冻电子显微镜解析了与人 TRPC6 同源四聚体复合物的结构，分辨率为 3.8Å，该复合物与新鉴定的高亲和力抑制剂 BTDM 结合。我们还呈现了分辨率为 4.4Å 的人源 TRPC3 结构。这些结构显示出双层架构，其中钟形胞质层保持跨膜层。胞质域的广泛的亚基间相互作用，包括 N 端锚蛋白重复和 C 端卷曲螺旋，有助于四聚体组装。高亲和力抑制剂 BTDM 楔入 S5-S6 孔域和电压传感器样域之间，抑制通道开放。我们的结构揭示了 TRPC 通道的分子结构，并为理解这些通道的机制提供了结构基础。
