2. Academic Validation
  3. Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2

Closed-state inactivation and pore-blocker modulation mechanisms of human CaV2.2

  • Cell Rep. 2021 Nov 2;37(5):109931. doi: 10.1016/j.celrep.2021.109931.
Yanli Dong 1,  Yiwei Gao 1,  Shuai Xu 2,  Yuhang Wang 3,  Zhuoya Yu 3,  Yue Li 3,  Bin Li 3,  Tian Yuan 2,  Bei Yang 3,  Xuejun Cai Zhang 3,  Daohua Jiang 4,  Zhuo Huang 5,  Yan Zhao 6
Affiliations

Affiliations

  • 1 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 2 State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China.
  • 3 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China.
  • 4 Laboratory of Soft Matter Physics, Institute of Physics, Chinese Academy of Sciences, Beijing 100190, China. Electronic address: jiangdh@iphy.ac.cn.
  • 5 State Key Laboratory of Natural and Biomimetic Drugs, Department of Molecular and Cellular Pharmacology, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China; IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China. Electronic address: huangz@hsc.pku.edu.cn.
  • 6 National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China; State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China; College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China. Electronic address: zhaoy@ibp.ac.cn.
PMID: 34731621 DOI: 10.1016/j.celrep.2021.109931
Abstract

N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human CaV2.2 complex in apo, ziconotide-bound, and two CaV2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP2) molecule, which is distinct from the other three VSDs of CaV2.2, as well as activated VSDs observed in previous structures of CaV channels. This structure reveals the molecular basis for the unique inactivation process of CaV2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II-III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.

Keywords

Ca(V)2.2; N-type; channel blocker; closed-state inactivation; neurotransmitter release; presynapse; voltage-gated calcium channel; ziconotide.

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