Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors

Yiqing Wei, Zhuoya Yu, Lili Wang, Xiaojing Li, Na Li, Qinru Bai, Yuhang Wang, Renjie Li, Yufei Meng, Hao Xu, Xianping Wang, Yanli Dong, Zhuo Huang (), Xuejun Cai Zhang () and Yan Zhao ()
Additional contact information
Yiqing Wei: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Zhuoya Yu: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Lili Wang: School of Pharmaceutical Sciences, Peking University Health Science Center
Xiaojing Li: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Na Li: Beijing Chaoyang Hospital, Capital Medical University
Qinru Bai: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Yuhang Wang: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Renjie Li: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Yufei Meng: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Hao Xu: University of Science and Technology of China
Xianping Wang: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Yanli Dong: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Zhuo Huang: School of Pharmaceutical Sciences, Peking University Health Science Center
Xuejun Cai Zhang: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
Yan Zhao: CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract The voltage-gated calcium channel CaV1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of CaV1.2 are involved in brain and heart diseases. Pharmacological inhibition of CaV1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of CaV1.2 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 S6II, S6III, and S6IV helices and forms extensive hydrophobic interactions with CaV1.2. Our structure elucidates that benidipine is located in the DIII-DIV fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5DIII, S6DIII, and S6DIV 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.

Date: 2024
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DOI: 10.1038/s41467-024-47116-8

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