8WE8

Human L-type voltage-gated calcium channel Cav1.2 in the presence of calciseptine, amlodipine and pinaverium at 2.9 Angstrom resolution

Summary for 8WE8

• Entry DOI: 10.2210/pdb8we8/pdb
• EMDB information: 37474
• Descriptor: Voltage-dependent L-type calcium channel subunit alpha-1C, 2-acetamido-2-deoxy-beta-D-glucopyranose, [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate, ... (13 entities in total)
• Functional Keywords: cav1.2, channels, calcium ion-selective, transport protein, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 4
• Total formula weight: 440820.51

Authors

Gao, S.,Yao, X.,Yan, N. (deposition date: 2023-09-17, release date: 2023-12-06, Last modification date: 2025-06-18)

Primary citation

Gao, S.,Yao, X.,Chen, J.,Huang, G.,Fan, X.,Xue, L.,Li, Z.,Wu, T.,Zheng, Y.,Huang, J.,Jin, X.,Wang, Y.,Wang, Z.,Yu, Y.,Liu, L.,Pan, X.,Song, C.,Yan, N.
Structural basis for human Ca v 1.2 inhibition by multiple drugs and the neurotoxin calciseptine.
Cell, 186:5363-5374.e16, 2023

PubMed Abstract: Ca1.2 channels play crucial roles in various neuronal and physiological processes. Here, we present cryo-EM structures of human Ca1.2, both in its apo form and in complex with several drugs, as well as the peptide neurotoxin calciseptine. Most structures, apo or bound to calciseptine, amlodipine, or a combination of amiodarone and sofosbuvir, exhibit a consistent inactivated conformation with a sealed gate, three up voltage-sensing domains (VSDs), and a down VSD. Calciseptine sits on the shoulder of the pore domain, away from the permeation path. In contrast, when pinaverium bromide, an antispasmodic drug, is inserted into a cavity reminiscent of the IFM-binding site in Na channels, a series of structural changes occur, including upward movement of VSD coupled with dilation of the selectivity filter and its surrounding segments in repeat III. Meanwhile, S4-5 merges with S5 to become a single helix, resulting in a widened but still non-conductive intracellular gate.

PubMed: 37972591
DOI: 10.1016/j.cell.2023.10.007

Experimental method

ELECTRON MICROSCOPY (2.9 Å)