Structural basis for human Ca_v1.2 inhibition by multiple drugs and the neurotoxin calciseptine

Ca_v1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Ca_v1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSD_II. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Na_v channels, a series of structural changes occur, including upward movement of VSD_II coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5_III merges with S5_III to become a single helix, resulting in a widened but still non-conductive intracellular gate.