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Structure paper

TitleStructure of human Ca2.2 channel blocked by the painkiller ziconotide.
Journal, issue, pagesNature, Vol. 596, Issue 7870, Page 143-147, Year 2021
Publish dateJul 7, 2021
AuthorsShuai Gao / Xia Yao / Nieng Yan /
PubMed AbstractThe neuronal-type (N-type) voltage-gated calcium (Ca) channels, which are designated Ca2.2, have an important role in the release of neurotransmitters. Ziconotide is a Ca2.2-specific peptide pore ...The neuronal-type (N-type) voltage-gated calcium (Ca) channels, which are designated Ca2.2, have an important role in the release of neurotransmitters. Ziconotide is a Ca2.2-specific peptide pore blocker that has been clinically used for treating intractable pain. Here we present cryo-electron microscopy structures of human Ca2.2 (comprising the core α1 and the ancillary α2δ-1 and β3 subunits) in the presence or absence of ziconotide. Ziconotide is thoroughly coordinated by helices P1 and P2, which support the selectivity filter, and the extracellular loops (ECLs) in repeats II, III and IV of α1. To accommodate ziconotide, the ECL of repeat III and α2δ-1 have to tilt upward concertedly. Three of the voltage-sensing domains (VSDs) are in a depolarized state, whereas the VSD of repeat II exhibits a down conformation that is stabilized by Ca2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Ca2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Ca channels.
External linksNature / PubMed:34234349 / PubMed Central
MethodsEM (single particle)
Resolution3.0 - 3.1 Å
Structure data

23867

7mix

EMDB-23867, PDB-7mix:
Human N-type voltage-gated calcium channel Cav2.2 in the presence of ziconotide at 3.0 Angstrom resolution
Method: EM (single particle) / Resolution: 3.0 Å

23868

7miy

EMDB-23868, PDB-7miy:
Human N-type voltage-gated calcium channel Cav2.2 at 3.1 Angstrom resolution
Method: EM (single particle) / Resolution: 3.1 Å

Chemicals

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

ChemComp-CA:
Unknown entry

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

ChemComp-CLR:
CHOLESTEROL

ChemComp-3PE:
1,2-Distearoyl-sn-glycerophosphoethanolamine / phospholipid*YM

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

Source
  • homo sapiens (human)
  • conus magus (magus cone)
KeywordsTRANSPORT PROTEIN/TOXIN / Cav2.2 / Channels / Calcium Ion-Selective / TRANSPORT PROTEIN-TOXIN complex / drugs / TRANSPORT PROTEIN

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