Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277

Katrien Willegems, Jodene Eldstrom, Efthimios Kyriakis, Fariba Ataei, Harutyun Sahakyan, Ying Dou, Sophia Russo, Filip Petegem () and David Fedida ()
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Katrien Willegems: University of British Columbia
Jodene Eldstrom: University of British Columbia
Efthimios Kyriakis: University of British Columbia
Fariba Ataei: University of British Columbia
Harutyun Sahakyan: National Institutes for Health
Ying Dou: University of British Columbia
Sophia Russo: University of British Columbia
Filip Petegem: University of British Columbia
David Fedida: University of British Columbia

Nature Communications, 2022, vol. 13, issue 1, 1-17

Abstract: 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 Ca2+/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.

Date: 2022
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DOI: 10.1038/s41467-022-31526-7

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