7MIX

Human N-type voltage-gated calcium channel Cav2.2 in the presence of ziconotide at 3.0 Angstrom resolution

Summary for 7MIX

• Entry DOI: 10.2210/pdb7mix/pdb
• EMDB information: 23867 23868
• Descriptor: Voltage-dependent N-type calcium channel subunit alpha-1B, CHOLESTEROL HEMISUCCINATE, CHOLESTEROL, ... (13 entities in total)
• Functional Keywords: cav2.2, channels, calcium ion-selective, transport protein-toxin complex, drugs, transport protein/toxin
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 453709.62

Authors

Yan, N.,Gao, S.,Yao, X. (deposition date: 2021-04-18, release date: 2021-07-07, Last modification date: 2024-11-13)

Primary citation

Gao, S.,Yao, X.,Yan, N.
Structure of human Ca v 2.2 channel blocked by the painkiller ziconotide.
Nature, 596:143-147, 2021

PubMed Abstract: 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.

PubMed: 34234349
DOI: 10.1038/s41586-021-03699-6

Experimental method

ELECTRON MICROSCOPY (3 Å)