2. Academic Validation
  3. Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine

Structural basis for human Cav1.2 inhibition by multiple drugs and the neurotoxin calciseptine

  • Cell. 2023 Nov 8:S0092-8674(23)01106-6. doi: 10.1016/j.cell.2023.10.007.
Shuai Gao 1,  Xia Yao 2,  Jiaofeng Chen 3,  Gaoxingyu Huang 4,  Xiao Fan 5,  Lingfeng Xue 6,  Zhangqiang Li 3,  Tong Wu 3,  Yupeng Zheng 7,  Jian Huang 5,  Xueqin Jin 3,  Yan Wang 8,  Zhifei Wang 8,  Yong Yu 8,  Lei Liu 7,  Xiaojing Pan 9,  Chen Song 10,  Nieng Yan 11
Affiliations

Affiliations

  • 1 Department of Urology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. Electronic address: gaoshuai812@whu.edu.cn.
  • 2 Department of Urology, Zhongnan Hospital of Wuhan University, TaiKang Center for Life and Medical Sciences, School of Pharmaceutical Sciences, Wuhan University, Wuhan 430071, China; Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 3 Beijing Frontier Research Center for Biological Structures, Tsinghua-Peking Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
  • 4 Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Institute of Biology, Westlake Institute for Advanced Study, Zhejiang Provincial Laboratory of Life Sciences and Biomedicine, Hangzhou, Zhejiang 310024, China.
  • 5 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
  • 6 Center for Quantitative Biology, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 7 Tsinghua-Peking Center for Life Sciences, Ministry of Education Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Center for Synthetic and Systems Biology, Department of Chemistry, Tsinghua University, Beijing 100084, China.
  • 8 Department of Biological Sciences, St. John's University, Queens, NY 11439, USA.
  • 9 Beijing Frontier Research Center for Biological Structures, Tsinghua-Peking Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Shenzhen Medical Academy of Research and Translation, Shenzhen, Guangdong 518107, China.
  • 10 Center for Quantitative Biology, Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China. Electronic address: c.song@pku.edu.cn.
  • 11 Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA; Beijing Frontier Research Center for Biological Structures, Tsinghua-Peking Center for Life Sciences, State Key Laboratory of Membrane Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China; Shenzhen Medical Academy of Research and Translation, Shenzhen, Guangdong 518107, China. Electronic address: nyan@tsinghua.edu.cn.
PMID: 37972591 DOI: 10.1016/j.cell.2023.10.007
Abstract

CAv1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human CAv1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSDII. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Nav channels, a series of structural changes occur, including upward movement of VSDII coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5III merges with S5III to become a single helix, resulting in a widened but still non-conductive intracellular gate.

Keywords

Ca(v)1.2; L-type calcium channels; LTCC; amiodarone; amlodipine; calciseptine; channel inactivation; pinaverium bromide; sofosbuvir; voltage-gated calcium channels.

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