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Structure of human Cav2.2 channel blocked by the painkiller ziconotide

Author

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  • Shuai Gao

    (Princeton University)

  • Xia Yao

    (Princeton University)

  • Nieng Yan

    (Princeton University)

Abstract

The neuronal-type (N-type) voltage-gated calcium (Cav) channels, which are designated Cav2.2, have an important role in the release of neurotransmitters1–3. Ziconotide is a Cav2.2-specific peptide pore blocker that has been clinically used for treating intractable pain4–6. Here we present cryo-electron microscopy structures of human Cav2.2 (comprising the core α1 and the ancillary α2δ-1 and β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Cav2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Cav2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Cav channels.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:nature:v:596:y:2021:i:7870:d:10.1038_s41586-021-03699-6
    DOI: 10.1038/s41586-021-03699-6
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    Cited by:

    1. Yiwei Gao & Shuai Xu & Xiaoli Cui & Hao Xu & Yunlong Qiu & Yiqing Wei & Yanli Dong & Boling Zhu & Chao Peng & Shiqi Liu & Xuejun Cai Zhang & Jianyuan Sun & Zhuo Huang & Yan Zhao, 2023. "Molecular insights into the gating mechanisms of voltage-gated calcium channel CaV2.3," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    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. Xia Yao & Yan Wang & Zhifei Wang & Xiao Fan & Di Wu & Jian Huang & Alexander Mueller & Sarah Gao & Miaohui Hu & Carol V. Robinson & Yong Yu & Shuai Gao & Nieng Yan, 2022. "Structures of the R-type human Cav2.3 channel reveal conformational crosstalk of the intracellular segments," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    4. 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.
    5. Woori Ko & Euna Lee & Jung-Eun Kim & Hyun-Ho Lim & Byung-Chang Suh, 2024. "The plasma membrane inner leaflet PI(4,5)P2 is essential for the activation of proton-activated chloride channels," Nature Communications, Nature, vol. 15(1), pages 1-15, December.

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