8HLP

Cryo-EM structure of human high-voltage activated L-type calcium channel CaV1.2 (apo)

Summary for 8HLP

• Entry DOI: 10.2210/pdb8hlp/pdb
• EMDB information: 34880
• Descriptor: Voltage-dependent L-type calcium channel subunit alpha, Voltage-dependent calcium channel subunit alpha-2/delta-1, Isoform 2c of Voltage-dependent L-type calcium channel subunit beta-2, ... (7 entities in total)
• Functional Keywords: apo state, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 440817.40

Authors

Wei, Y.,Yu, Z.,Zhao, Y. (deposition date: 2022-11-30, release date: 2024-04-24, Last modification date: 2025-06-04)

Primary citation

Wei, Y.,Yu, Z.,Wang, L.,Li, X.,Li, N.,Bai, Q.,Wang, Y.,Li, R.,Meng, Y.,Xu, H.,Wang, X.,Dong, Y.,Huang, Z.,Zhang, X.C.,Zhao, Y.
Structural bases of inhibitory mechanism of Ca V 1.2 channel inhibitors.
Nat Commun, 15:2772-2772, 2024

PubMed Abstract: The voltage-gated calcium channel Ca1.2 is essential for cardiac and vessel smooth muscle contractility and brain function. Accumulating evidence demonstrates that malfunctions of Ca1.2 are involved in brain and heart diseases. Pharmacological inhibition of Ca1.2 is therefore of therapeutic value. Here, we report cryo-EM structures of Ca1.2 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, S6, and S6 helices and forms extensive hydrophobic interactions with Ca1.2. Our structure elucidates that benidipine is located in the D-D fenestration site. Its hydrophobic sidechain, phenylpiperidine, is positioned at the exterior of the pore domain and cradled within a hydrophobic pocket formed by S5, S6, and S6 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.

PubMed: 38555290
DOI: 10.1038/s41467-024-47116-8

Experimental method

ELECTRON MICROSCOPY (3.5 Å)