Structure of human Cav2.2 channel blocked by the painkiller ziconotide

The neuronal-type (N-type) voltage-gated calcium (Ca-v) channels, which are designated Ca(v)2.2, have an important role in the release of neurotransmitters(1-3). Ziconotide is a Ca(v)2.2-specific peptide pore blocker that has been clinically used for treating intractable pain(4-6). Here we present cryo-electron microscopy structures of human Ca(v)2.2 (comprising the core alpha 1 and the ancillary alpha 2 delta-1 and beta 3 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 alpha 1. To accommodate ziconotide, the ECL of repeat III and alpha 2 delta-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 Ca(v)2-unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule. Our studies reveal the molecular basis for Ca(v)2.2-specific pore blocking by ziconotide and establish the framework for investigating electromechanical coupling in Ca-v channels.

Automated summary

This study reveals the molecular basis for Ca(v)2.2-specific pore blocking by ziconotide through coordinated structural changes in the presence of the peptide. The depolarized state of three voltage-sensing domains and the stabilizing effect of unique intracellular segments and a phosphatidylinositol 4,5-bisphosphate molecule in repeat II VSD are also highlighted. These findings establish a framework for investigating electromechanical coupling in Ca-v channels.