8HMB
Cryo-EM structure of human high-voltage activated L-type calcium channel CaV1.2 in complex with benidipine (BEN)
This is a non-PDB format compatible entry.
Summary for 8HMB
Entry DOI | 10.2210/pdb8hmb/pdb |
EMDB information | 34892 |
Descriptor | Isoform 2c of Voltage-dependent L-type calcium channel subunit beta-2, Voltage-dependent L-type calcium channel subunit alpha, Voltage-dependent calcium channel subunit alpha-2/delta-1, ... (8 entities in total) |
Functional Keywords | ben bound state, membrane protein |
Biological source | Homo sapiens (human) More |
Total number of polymer chains | 3 |
Total formula weight | 442509.22 |
Authors | |
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 Cited by 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: 38555290DOI: 10.1038/s41467-024-47116-8 PDB entries with the same primary citation |
Experimental method | ELECTRON MICROSCOPY (3.3 Å) |
Structure validation
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