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Structure paper

TitleClosed-state inactivation and pore-blocker modulation mechanisms of human Ca2.2.
Journal, issue, pagesCell Rep, Vol. 37, Issue 5, Page 109931, Year 2021
Publish dateNov 2, 2021
AuthorsYanli 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 AbstractN-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 linksCell Rep / PubMed:34731621
MethodsEM (single particle)
Resolution2.8 - 3.3 Å
Structure data

EMDB-31958, PDB-7vfs:
Human N-type voltage gated calcium channel CaV2.2-alpha2/delta1-beta1 complex, apo state
Method: EM (single particle) / Resolution: 2.8 Å

EMDB-31959, PDB-7vfu:
Human N-type voltage gated calcium channel CaV2.2-alpha2/delta1-beta1 complex, bound to ziconotide
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-31960, PDB-7vfv:
Human N-type voltage gated calcium channel CaV2.2-alpha2/delta1-beta1 complex, bound to PD173212
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-31961, PDB-7vfw:
Human N-type voltage gated calcium channel CaV2.2-alpha2/delta1-beta1 complex, bound to CaV2.2-blocker1
Method: EM (single particle) / Resolution: 3.3 Å

Chemicals

ChemComp-R16:
HEXADECANE

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-PT5:
[(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho / phospholipid*YM

ChemComp-CA:
Unknown entry

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose

ChemComp-6IX:
(2~{S})-~{N}-[(2~{S})-1-(~{tert}-butylamino)-1-oxidanylidene-3-(4-phenylmethoxyphenyl)propan-2-yl]-2-[(4-~{tert}-butylphenyl)methyl-methyl-amino]-4-methyl-pentanamide

ChemComp-6I7:
5-(4-chlorophenyl)-1-(2-methoxyphenyl)-3-(2,2,6,6-tetramethyloxan-4-yl)pyrazole

Source
  • homo sapiens (human)
  • conus magus (magus cone)
KeywordsMEMBRANE PROTEIN / Voltage gated calcium channel / N-type / complex

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