Cryo-EM structures of the human CaV2.2 complex reveal a resting-state conformation of the second voltage-sensing domain and the molecular basis for its unique closed-state inactivation process.
The cryo-EM structure of the human CaV2.2 complex provides a molecular foundation for developing new state-dependent blockers for chronic pain treatment.
N-type voltage-gated calcium (CaV) channels mediate Ca2+ influx at presynaptic terminals in response to action potentials and play vital roles in synaptogenesis, release of neurotransmitters, and nociceptive transmission. Here, we elucidate a cryo-electron microscopy (cryo-EM) structure of the human CaV2.2 complex in apo, ziconotide-bound, and two CaV2.2-specific pore blockers-bound states. The second voltage-sensing domain (VSD) is captured in a resting-state conformation, trapped by a phosphatidylinositol 4,5-bisphosphate (PIP2) molecule, which is distinct from the other three VSDs of CaV2.2, as well as activated VSDs observed in previous structures of CaV channels. This structure reveals the molecular basis for the unique inactivation process of CaV2.2 channels, in which the intracellular gate formed by S6 helices is closed and a W-helix from the domain II–III linker stabilizes closed-state inactivation. The structures of this inactivated, drug-bound complex lay a solid foundation for developing new state-dependent blockers for treatment of chronic pain.
Dong et al. (2021) studied this question. Cryo-EM structures of the human CaV2.2 complex reveal a resting-state conformation of the second voltage-sensing domain and the molecular basis for its unique closed-state inactivation process.