9AYG
Cryo-EM structure of apo state human Cav3.2
Summary for 9AYG
Entry DOI | 10.2210/pdb9ayg/pdb |
EMDB information | 43991 |
Descriptor | Voltage-dependent T-type calcium channel subunit alpha-1H, 2-acetamido-2-deoxy-beta-D-glucopyranose, CALCIUM ION, ... (6 entities in total) |
Functional Keywords | cav3.2, voltage gated calcium channel, cryo-em, transport protein |
Biological source | Homo sapiens (human) More |
Total number of polymer chains | 1 |
Total formula weight | 240449.34 |
Authors | |
Primary citation | Huang, 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: 38605177DOI: 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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