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

Author

Listed:
  • Katrien Willegems

    (University of British Columbia
    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)

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.

Suggested Citation

  • Katrien Willegems & Jodene Eldstrom & Efthimios Kyriakis & Fariba Ataei & Harutyun Sahakyan & Ying Dou & Sophia Russo & Filip Petegem & David Fedida, 2022. "Structural and electrophysiological basis for the modulation of KCNQ1 channel currents by ML277," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31526-7
    DOI: 10.1038/s41467-022-31526-7
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    References listed on IDEAS

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    1. Panpan Hou & Jodene Eldstrom & Jingyi Shi & Ling Zhong & Kelli McFarland & Yuan Gao & David Fedida & Jianmin Cui, 2017. "Inactivation of KCNQ1 potassium channels reveals dynamic coupling between voltage sensing and pore opening," Nature Communications, Nature, vol. 8(1), pages 1-11, December.
    2. Panpan Hou & Po Wei Kang & Audrey Deyawe Kongmeneck & Nien-Du Yang & Yongfeng Liu & Jingyi Shi & Xianjin Xu & Kelli McFarland White & Mark A. Zaydman & Marina A. Kasimova & Guiscard Seebohm & Ling Zho, 2020. "Two-stage electro–mechanical coupling of a KV channel in voltage-dependent activation," Nature Communications, Nature, vol. 11(1), pages 1-14, December.
    3. Karen Mruk & William R Kobertz, 2009. "Discovery of a Novel Activator of KCNQ1-KCNE1 K+ Channel Complexes," PLOS ONE, Public Library of Science, vol. 4(1), pages 1-9, January.
    4. Björn C. Schroeder & Siegfried Waldegger & Susanne Fehr & Markus Bleich & Richard Warth & Rainer Greger & Thomas J. Jentsch, 2000. "A constitutively open potassium channel formed by KCNQ1 and KCNE3," Nature, Nature, vol. 403(6766), pages 196-199, January.
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    Cited by:

    1. Demin Ma & Yueming Zheng & Xiaoxiao Li & Xiaoyu Zhou & Zhenni Yang & Yan Zhang & Long Wang & Wenbo Zhang & Jiajia Fang & Guohua Zhao & Panpan Hou & Fajun Nan & Wei Yang & Nannan Su & Zhaobing Gao & Ji, 2023. "Ligand activation mechanisms of human KCNQ2 channel," Nature Communications, Nature, vol. 14(1), pages 1-13, December.

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