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Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors

Author

Listed:
  • Yiqing Wei

    (CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Zhuoya Yu

    (CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of 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
    University of 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
    University of Chinese Academy of Sciences)

  • Yuhang Wang

    (CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Renjie Li

    (CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

  • Yufei Meng

    (CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of 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
    University of Chinese Academy of Sciences)

  • Yan Zhao

    (CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences
    University of Chinese Academy of Sciences)

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.

Suggested Citation

  • 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 & Yan Zhao, 2024. "Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47116-8
    DOI: 10.1038/s41467-024-47116-8
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    References listed on IDEAS

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    1. Zhou Chen & Abhisek Mondal & Fayal Abderemane-Ali & Seil Jang & Sangeeta Niranjan & José L. Montaño & Balyn W. Zaro & Daniel L. Minor, 2023. "EMC chaperone–CaV structure reveals an ion channel assembly intermediate," Nature, Nature, vol. 619(7969), pages 410-419, July.
    2. 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 & Yan Zhao, 2022. "Structure, gating, and pharmacology of human CaV3.3 channel," Nature Communications, Nature, vol. 13(1), pages 1-9, December.
    3. Luke L. McGoldrick & Appu K. Singh & Kei Saotome & Maria V. Yelshanskaya & Edward C. Twomey & Robert A. Grassucci & Alexander I. Sobolevsky, 2018. "Opening of the human epithelial calcium channel TRPV6," Nature, Nature, vol. 553(7687), pages 233-237, January.
    4. Lin Tang & Tamer M. Gamal El-Din & Jian Payandeh & Gilbert Q. Martinez & Teresa M. Heard & Todd Scheuer & Ning Zheng & William A. Catterall, 2014. "Structural basis for Ca2+ selectivity of a voltage-gated calcium channel," Nature, Nature, vol. 505(7481), pages 56-61, January.
    5. Shuai Gao & Xia Yao & Nieng Yan, 2021. "Structure of human Cav2.2 channel blocked by the painkiller ziconotide," Nature, Nature, vol. 596(7870), pages 143-147, August.
    6. Lin Tang & Tamer M. Gamal El-Din & Teresa M. Swanson & David C. Pryde & Todd Scheuer & Ning Zheng & William A. Catterall, 2016. "Structural basis for inhibition of a voltage-gated Ca2+ channel by Ca2+ antagonist drugs," Nature, Nature, vol. 537(7618), pages 117-121, September.
    7. Yanyu Zhao & Gaoxingyu Huang & Qiurong Wu & Kun Wu & Ruiqi Li & Jianlin Lei & Xiaojing Pan & Nieng Yan, 2019. "Cryo-EM structures of apo and antagonist-bound human Cav3.1," Nature, Nature, vol. 576(7787), pages 492-497, December.
    8. Jianping Wu & Zhen Yan & Zhangqiang Li & Xingyang Qian & Shan Lu & Mengqiu Dong & Qiang Zhou & Nieng Yan, 2016. "Structure of the voltage-gated calcium channel Cav1.1 at 3.6 Å resolution," Nature, Nature, vol. 537(7619), pages 191-196, September.
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