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

Cell Reports

卷:37

Shuai Xu¹  Bei Yang¹  Yue Li¹  Yan Zhao¹  Daohua Jiang¹  Yiwei Gao²  Zhuoya Yu²  Tian Yuan³  Yanli Dong³  Xuejun Cai Zhang³  Zhuo Huang³  Yuhang Wang³  Bin Li⁴ 

[1] College of Life Sciences, University of Chinese Academy of Sciences, Beijing 100049, China;

[2] State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China;

[3] National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing 100101, China;

[4] 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;

关键词: CaV2.2;    closed-state inactivation;    channel blocker;    ziconotide;    N-type;    voltage-gated calcium channel;   

DOI  :  

来源: DOAJ

【 摘 要 】

Summary: 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.

【 授权许可】

Unknown