Structure of human Ca2.2 channel blocked by the painkiller ziconotide. Author Shuai Gao, Xia Yao, Nieng Yan Publication Year 2021 Type Journal Article 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. Keywords Humans, Models, Molecular, Protein Conformation, Phosphatidylinositol 4,5-Diphosphate, Cryoelectron Microscopy, Protein Stability, Calcium Channel Blockers, Analgesics, Non-Narcotic, Calcium Channels, N-Type, omega-Conotoxins Journal Nature Volume 596 Issue 7870 Pages 143-147 Date Published 2021 Aug ISSN Number 1476-4687 DOI 10.1038/s41586-021-03699-6 Alternate Journal Nature PMCID PMC8529174 PMID 34234349 PubMedPubMed CentralGoogle ScholarBibTeXEndNote X3 XML