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Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors
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Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors
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Journal Article
Structural bases of inhibitory mechanism of CaV1.2 channel inhibitors
2024
Overview
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.
CaV1.2 is crucial in cardiac, vascular and neuronal function, serving as a target for many drugs. Here, authors identify the binding site of herb-derived drug tetrandrine, and explore inhibitory mechanism of L/T-type selective DHP drug benidipine.
