Structural bases of inhibitory mechanism of Ca_V1.2 channel inhibitors

The voltage-gated calcium channel Ca(V)1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca(V)1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca(V)1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca(V)1.2 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(V)1.2. 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.