Structure, gating, and pharmacology of human CaV3.3 channel

Lingli He, Zhuoya Yu, Ze Geng, Zhuo Huang, Changjiang Zhang, Yanli Dong, Yiwei Gao, Yuhang Wang, Qihao Chen, Le Sun, Xinyue Ma, Bo Huang, Xiaoqun Wang and Yan Zhao ()
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Lingli He: Chinese Academy of Sciences
Zhuoya Yu: Chinese Academy of Sciences
Ze Geng: Peking University Health Science Center
Zhuo Huang: Peking University Health Science Center
Changjiang Zhang: Chinese Academy of Sciences
Yanli Dong: Chinese Academy of Sciences
Yiwei Gao: Chinese Academy of Sciences
Yuhang Wang: Chinese Academy of Sciences
Qihao Chen: Chinese Academy of Sciences
Le Sun: Capital Medical University
Xinyue Ma: Peking University Health Science Center
Bo Huang: StoneWise Ltd.
Xiaoqun Wang: Chinese Academy of Sciences
Yan Zhao: Chinese Academy of Sciences

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type CaV3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. CaV3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type CaV channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the CaV3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.

Date: 2022
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DOI: 10.1038/s41467-022-29728-0

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