Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors

• Published in: Nature communications 2024-03, Vol.15 (1), p.2772-2772, Article 2772
• Main Authors: Wei, Yiqing, Yu, Zhuoya, Wang, Lili, Li, Xiaojing, Li, Na, Bai, Qinru, Wang, Yuhang, Li, Renjie, Meng, Yufei, Xu, Hao, Wang, Xianping, Dong, Yanli, Huang, Zhuo, Zhang, Xuejun Cai, Zhao, Yan
• Format: Article
• Language: English
• Subjects: 101/28; 631/378/1689; 631/45/269; 631/535/1258/1259; 631/57; 82/80; 82/83; 9/74; Antihypertensives; Binding sites; Blood vessels; Brain; Calcium; Calcium channels; Calcium channels (L-type); Calcium channels (T-type); Calcium channels (voltage-gated); Cardiac muscle; Cardiovascular diseases; Channel gating; Channels; Design optimization; Drugs; Heart diseases; Helices; Humanities and Social Sciences; Hydrophobicity; Hypertension; Inhibitors; Laboratories; Life sciences; multidisciplinary; Muscle contraction; Mutation; Optimization; Science; Science (multidisciplinary); Smooth muscle; Tetrandrine
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-47116-8

The voltage-gated calcium channel Ca V 1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca V 1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca V 1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca V 1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6 II , S6 III , and S6 IV helices and forms extensive hydrophobic interactions with Ca V 1.2. Our structure elucidates that benidipine is located in the D III -D IV fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5 DIII , S6 DIII , and S6 DIV helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels. CaV1.2 is crucial in cardiac, vascular and neuronal function, serving as a target for many drugs. Here, authors identify the binding site of herb-derived drug tetrandrine, and explore inhibitory mechanism of L/T-type selective DHP drug benidipine.