7TCI

Structure of Xenopus KCNQ1-CaM in complex with ML277

Summary for 7TCI

• Entry DOI: 10.2210/pdb7tci/pdb
• EMDB information: 25813 25816
• Descriptor: Potassium voltage-gated channel subfamily KQT member 1, Calmodulin-1, (2R)-N-[4-(4-methoxyphenyl)-1,3-thiazol-2-yl]-1-(4-methylbenzene-1-sulfonyl)piperidine-2-carboxamide, ... (4 entities in total)
• Functional Keywords: activator, ion channel, transport protein-activator complex, transport protein/activator
• Biological source: Xenopus laevis (African clawed frog); More
• Total number of polymer chains: 8
• Total formula weight: 320431.08

Authors

Willegems, K.,Kyriakis, E.,Van Petegem, F.,Eldstrom, J.,Fedida, D. (deposition date: 2021-12-23, release date: 2022-07-06, Last modification date: 2025-05-28)

Primary citation

Willegems, K.,Eldstrom, J.,Kyriakis, E.,Ataei, F.,Sahakyan, H.,Dou, Y.,Russo, S.,Van Petegem, F.,Fedida, D.
Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277.
Nat Commun, 13:3760-3760, 2022

PubMed Abstract: The KCNQ1 ion channel plays critical physiological roles in electrical excitability and K recycling in organs including the heart, brain, and gut. Loss of function is relatively common and can cause sudden arrhythmic death, sudden infant death, epilepsy and deafness. Here, we report cryogenic electron microscopic (cryo-EM) structures of Xenopus KCNQ1 bound to Ca/Calmodulin, with and without the KCNQ1 channel activator, ML277. A single binding site for ML277 was identified, localized to a pocket lined by the S4-S5 linker, S5 and S6 helices of two separate subunits. Several pocket residues are not conserved in other KCNQ isoforms, explaining specificity. MD simulations and point mutations support this binding location for ML277 in open and closed channels and reveal that prevention of inactivation is an important component of the activator effect. Our work provides direction for therapeutic intervention targeting KCNQ1 loss of function pathologies including long QT interval syndrome and seizures.

PubMed: 35768468
DOI: 10.1038/s41467-022-31526-7

Experimental method

ELECTRON MICROSCOPY (3.9 Å)