7WLJ

CryoEM structure of human low-voltage activated T-type calcium channel Cav3.3 in complex with mibefradil (MIB)

Summary for 7WLJ

• Entry DOI: 10.2210/pdb7wlj/pdb
• EMDB information: 32585
• Descriptor: Voltage-dependent T-type calcium channel subunit alpha-1I, (1S,2S)-2-(2-{[3-(1H-benzimidazol-2-yl)propyl](methyl)amino}ethyl)-6-fluoro-1-(propan-2-yl)-1,2,3,4-tetrahydronaphthalen-2-yl methoxyacetate, 1,2-Distearoyl-sn-glycerophosphoethanolamine, ... (6 entities in total)
• Functional Keywords: mib, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 253011.83

Authors

He, L.,Yu, Z.,Dong, Y.,Chen, Q.,Zhao, Y. (deposition date: 2022-01-13, release date: 2022-05-04, Last modification date: 2024-11-06)

Primary citation

He, L.,Yu, Z.,Geng, Z.,Huang, Z.,Zhang, C.,Dong, Y.,Gao, Y.,Wang, Y.,Chen, Q.,Sun, L.,Ma, X.,Huang, B.,Wang, X.,Zhao, Y.
Structure, gating, and pharmacology of human Ca V 3.3 channel.
Nat Commun, 13:2084-2084, 2022

PubMed Abstract: The low-voltage activated T-type calcium channels regulate cellular excitability and oscillatory behavior of resting membrane potential which trigger many physiological events and have been implicated with many diseases. Here, we determine structures of the human T-type Ca3.3 channel, in the absence and presence of antihypertensive drug mibefradil, antispasmodic drug otilonium bromide and antipsychotic drug pimozide. Ca3.3 contains a long bended S6 helix from domain III, with a positive charged region protruding into the cytosol, which is critical for T-type Ca channel activation at low voltage. The drug-bound structures clearly illustrate how these structurally different compounds bind to the same central cavity inside the Ca3.3 channel, but are mediated by significantly distinct interactions between drugs and their surrounding residues. Phospholipid molecules penetrate into the central cavity in various extent to shape the binding pocket and play important roles in stabilizing the inhibitor. These structures elucidate mechanisms of channel gating, drug recognition, and actions, thus pointing the way to developing potent and subtype-specific drug for therapeutic treatments of related disorders.

PubMed: 35440630
DOI: 10.1038/s41467-022-29728-0

Experimental method

ELECTRON MICROSCOPY (3.9 Å)