Structure of human Ca2.2 channel blocked by the painkiller ziconotide.

TitleStructure of human Ca2.2 channel blocked by the painkiller ziconotide.
Publication TypeJournal Article
Year of Publication2021
AuthorsGao, S, Yao, X, Yan, N
JournalNature
Volume596
Issue7870
Pagination143-147
Date Published2021 08
ISSN1476-4687
KeywordsAnalgesics, Non-Narcotic, Calcium Channel Blockers, Calcium Channels, N-Type, Cryoelectron Microscopy, Humans, Models, Molecular, omega-Conotoxins, Phosphatidylinositol 4,5-Diphosphate, Protein Conformation, Protein Stability
Abstract

<p>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.</p>

DOI10.1038/s41586-021-03699-6
Alternate JournalNature
PubMed ID34234349
Grant ListR01 GM130762 / GM / NIGMS NIH HHS / United States
5R01 GM130762 / NH / NIH HHS / United States