Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors

The voltage-gated calcium channel Ca_V1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca_V1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca_V1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca_V1.2 in the absence or presence of the antirheumatic drug tetrandrine or antihypertensive drug benidipine. Tetrandrine acts as a pore blocker in a pocket composed of S6^II, S6^III, and S6^IV helices and forms extensive hydrophobic interactions with Ca_V1.2. Our structure elucidates that benidipine is located in the D_III-D_IV fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5^DIII, S6^DIII, and S6^DIV helices, providing additional interactions to exert inhibitory effects on both L-type and T-type voltage gated calcium channels. These findings provide the structural foundation for the rational design and optimization of therapeutic inhibitors of voltage-gated calcium channels.