9AYK

Cryo-EM structure of human Cav3.2 with ML218

This is a non-PDB format compatible entry.

Summary for 9AYK

• Entry DOI: 10.2210/pdb9ayk/pdb
• EMDB information: 43994
• Descriptor: Voltage-dependent T-type calcium channel subunit alpha-1H, 3,5-dichloro-N-{[(1R,5S,6r)-3-(3,3-dimethylbutyl)-3-azabicyclo[3.1.0]hexan-6-yl]methyl}benzamide, 2-acetamido-2-deoxy-beta-D-glucopyranose, ... (7 entities in total)
• Functional Keywords: cav3.2, voltage gated calcium channel, cryo-em, transport protein, ml218
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 1
• Total formula weight: 240818.67

Authors

Fan, X.,Huang, J.,Yan, N. (deposition date: 2024-03-08, release date: 2024-04-24, Last modification date: 2024-10-30)

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

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

Experimental method

ELECTRON MICROSCOPY (3 Å)