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-Structure paper
Title | Closed-state inactivation and pore-blocker modulation mechanisms of human Ca2.2. |
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Journal, issue, pages | Cell Rep, Vol. 37, Issue 5, Page 109931, Year 2021 |
Publish date | Nov 2, 2021 |
Authors | Yanli Dong / Yiwei Gao / Shuai Xu / Yuhang Wang / Zhuoya Yu / Yue Li / Bin Li / Tian Yuan / Bei Yang / Xuejun Cai Zhang / Daohua Jiang / Zhuo Huang / Yan Zhao / |
PubMed Abstract | N-type voltage-gated calcium (Ca) channels mediate Ca influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and ...N-type voltage-gated calcium (Ca) channels mediate Ca 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 Ca2.2 complex in apo, ziconotide-bound, and two Ca2.2-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 (PIP) molecule, which is distinct from the other three VSDs of Ca2.2, as well as activated VSDs observed in previous structures of Ca channels. This structure reveals the molecular basis for the unique inactivation process of Ca2.2 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. |
External links | Cell Rep / PubMed:34731621 |
Methods | EM (single particle) |
Resolution | 2.8 - 3.3 Å |
Structure data | EMDB-31958, PDB-7vfs: EMDB-31959, PDB-7vfu: EMDB-31960, PDB-7vfv: EMDB-31961, PDB-7vfw: |
Chemicals | ChemComp-R16: ChemComp-Y01: ChemComp-PT5: ChemComp-CA: ChemComp-NAG: ChemComp-6IX: ChemComp-6I7: |
Source |
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Keywords | MEMBRANE PROTEIN / Voltage gated calcium channel / N-type / complex |