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Nature. 2019 Dec;576(7787):492-497. doi: 10.1038/s41586-019-1801-3. Epub 2019 Nov 25.

Cryo-EM structures of apo and antagonist-bound human Cav3.1.

Zhao Y1,2,3, Huang G3, Wu Q3, Wu K4, Li R4, Lei J5, Pan X3, Yan N6,7.

Author information

1
Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, Hangzhou, China.
2
Institute of Biology, Westlake Institute for Advanced Study, Hangzhou, China.
3
State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
4
Medical Research Center, Beijing Key Laboratory of Cardiopulmonary Cerebral Resuscitation, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China.
5
Technology Center for Protein Sciences, Ministry of Education Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, China.
6
State Key Laboratory of Membrane Biology, Beijing Advanced Innovation Center for Structural Biology, Tsinghua-Peking Joint Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China. nyan@princeton.edu.
7
Department of Molecular Biology, Princeton University, Princeton, NJ, USA. nyan@princeton.edu.

Abstract

Among the ten subtypes of mammalian voltage-gated calcium (Cav) channels, Cav3.1-Cav3.3 constitute the T-type, or the low-voltage-activated, subfamily, the abnormal activities of which are associated with epilepsy, psychiatric disorders and pain1-5. Here we report the cryo-electron microscopy structures of human Cav3.1 alone and in complex with a highly Cav3-selective blocker, Z9446,7, at resolutions of 3.3 Å and 3.1 Å, respectively. The arch-shaped Z944 molecule reclines in the central cavity of the pore domain, with the wide end inserting into the fenestration on the interface between repeats II and III, and the narrow end hanging above the intracellular gate like a plug. The structures provide the framework for comparative investigation of the distinct channel properties of different Cav subfamilies.

PMID:
31766050
DOI:
10.1038/s41586-019-1801-3

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