Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
Structural basis for human TRPC5 channel inhibition by two distinct inhibitors
Abstract TRPC5 channel is a non-selective cation channel that participates diverse physiological processes. Human TRPC5 inhibitors show promise in the treatment of anxiety disorder, depression and kidney disease. Despite the high relevance of TRPC5 to human health, its inhibitor binding pockets have not been fully characterized due to the lack of structural information, which greatly hinders structure-based drug discovery. Here we show cryo-EM structures of human TRPC5 in complex with two distinct inhibitors, namely clemizole and HC-070, to the resolution of 2.7 ?. Based on the high-quality cryo-EM maps, we uncover the different binding pockets and detailed binding modes for these two inhibitors. Clemizole binds inside the voltage sensor-like domain of each subunit, while HC-070 binds close to the ion channel pore and is wedged between adjacent subunits. Both of them exert the inhibitory function by stabilizing the ion channel in a closed state. These structures provide templates for further design and optimization of inhibitors targeting human TRPC5.
Wu Jing-Xiang、Kang Yunlu、Wei Miao、Song Kangcheng、Guo Wenjun、Chen Lei
State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine||Peking-Tsinghua Center for Life Sciences, Peking University||Academy for Advanced Interdisciplinary Studies, Peking UniversityState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular MedicineState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular MedicineState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular MedicineState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular MedicineState Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine||Peking-Tsinghua Center for Life Sciences, Peking University||Academy for Advanced Interdisciplinary Studies, Peking University
基础医学生物科学研究方法、生物科学研究技术生理学
Wu Jing-Xiang,Kang Yunlu,Wei Miao,Song Kangcheng,Guo Wenjun,Chen Lei.Structural basis for human TRPC5 channel inhibition by two distinct inhibitors[EB/OL].(2025-03-28)[2025-05-06].https://www.biorxiv.org/content/10.1101/2020.04.21.052910.点此复制
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