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9AYG

Cryo-EM structure of apo state human Cav3.2

Summary for 9AYG
Entry DOI10.2210/pdb9ayg/pdb
EMDB information43991
DescriptorVoltage-dependent T-type calcium channel subunit alpha-1H, 2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION, ... (6 entities in total)
Functional Keywordscav3.2, voltage gated calcium channel, cryo-em, transport protein
Biological sourceHomo sapiens (human)
More
Total number of polymer chains1
Total formula weight240449.34
Authors
Fan, X.,Huang, J.,Yan, N. (deposition date: 2024-03-07, release date: 2024-04-24, Last modification date: 2024-10-30)
Primary citationHuang, J.,Fan, X.,Jin, X.,Lyu, C.,Guo, Q.,Liu, T.,Chen, J.,Davakan, A.,Lory, P.,Yan, N.
Structural basis for human Ca v 3.2 inhibition by selective antagonists.
Cell Res., 34:440-450, 2024
Cited by
PubMed Abstract: The Ca3.2 subtype of T-type calcium channels has been targeted for developing analgesics and anti-epileptics for its role in pain and epilepsy. Here we present the cryo-EM structures of Ca3.2 alone and in complex with four T-type calcium channel selective antagonists with overall resolutions ranging from 2.8 Å to 3.2 Å. The four compounds display two binding poses. ACT-709478 and TTA-A2 both place their cyclopropylphenyl-containing ends in the central cavity to directly obstruct ion flow, meanwhile extending their polar tails into the IV-I fenestration. TTA-P2 and ML218 project their 3,5-dichlorobenzamide groups into the II-III fenestration and place their hydrophobic tails in the cavity to impede ion permeation. The fenestration-penetrating mode immediately affords an explanation for the state-dependent activities of these antagonists. Structure-guided mutational analysis identifies several key residues that determine the T-type preference of these drugs. The structures also suggest the role of an endogenous lipid in stabilizing drug binding in the central cavity.
PubMed: 38605177
DOI: 10.1038/s41422-024-00959-8
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3 Å)
Structure validation

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PDB entries from 2024-11-20

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