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Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design

Author

Listed:
  • Dihia Moussaoui

    (Sorbonne Université
    European Synchrotron Radiation Facility (ESRF))

  • James P. Robblee

    (University of Vermont)

  • Julien Robert-Paganin

    (Sorbonne Université)

  • Daniel Auguin

    (Sorbonne Université
    Université d’Orléans, INRAE)

  • Fabio Fisher

    (Imperial College London)

  • Patricia M. Fagnant

    (University of Vermont)

  • Jill E. Macfarlane

    (University of Vermont)

  • Julia Schaletzky

    (Drug Discovery Center)

  • Eddie Wehri

    (Drug Discovery Center)

  • Christoph Mueller-Dieckmann

    (European Synchrotron Radiation Facility (ESRF))

  • Jake Baum

    (Imperial College London
    Faculty of Medicine & Health, UNSW Sydney)

  • Kathleen M. Trybus

    (University of Vermont)

  • Anne Houdusse

    (Sorbonne Université)

Abstract

Malaria results in more than 500,000 deaths per year and the causative Plasmodium parasites continue to develop resistance to all known agents, including different antimalarial combinations. The class XIV myosin motor PfMyoA is part of a core macromolecular complex called the glideosome, essential for Plasmodium parasite mobility and therefore an attractive drug target. Here, we characterize the interaction of a small molecule (KNX-002) with PfMyoA. KNX-002 inhibits PfMyoA ATPase activity in vitro and blocks asexual blood stage growth of merozoites, one of three motile Plasmodium life-cycle stages. Combining biochemical assays and X-ray crystallography, we demonstrate that KNX-002 inhibits PfMyoA using a previously undescribed binding mode, sequestering it in a post-rigor state detached from actin. KNX-002 binding prevents efficient ATP hydrolysis and priming of the lever arm, thus inhibiting motor activity. This small-molecule inhibitor of PfMyoA paves the way for the development of alternative antimalarial treatments.

Suggested Citation

  • Dihia Moussaoui & James P. Robblee & Julien Robert-Paganin & Daniel Auguin & Fabio Fisher & Patricia M. Fagnant & Jill E. Macfarlane & Julia Schaletzky & Eddie Wehri & Christoph Mueller-Dieckmann & Ja, 2023. "Mechanism of small molecule inhibition of Plasmodium falciparum myosin A informs antimalarial drug design," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38976-7
    DOI: 10.1038/s41467-023-38976-7
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    References listed on IDEAS

    as
    1. Vicente J. Planelles-Herrero & James J. Hartman & Julien Robert-Paganin & Fady I. Malik & Anne Houdusse, 2017. "Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    2. Julien Robert-Paganin & James P. Robblee & Daniel Auguin & Thomas C. A. Blake & Carol S. Bookwalter & Elena B. Krementsova & Dihia Moussaoui & Michael J. Previs & Guillaume Jousset & Jake Baum & Kathl, 2019. "Plasmodium myosin A drives parasite invasion by an atypical force generating mechanism," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    3. Julien Robert-Paganin & Xiao-Ping Xu & Mark F. Swift & Daniel Auguin & James P. Robblee & Hailong Lu & Patricia M. Fagnant & Elena B. Krementsova & Kathleen M. Trybus & Anne Houdusse & Niels Volkmann , 2021. "The actomyosin interface contains an evolutionary conserved core and an ancillary interface involved in specificity," Nature Communications, Nature, vol. 12(1), pages 1-11, December.
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    Cited by:

    1. Daniel Auguin & Julien Robert-Paganin & Stéphane Réty & Carlos Kikuti & Amandine David & Gabriele Theumer & Arndt W. Schmidt & Hans-Joachim Knölker & Anne Houdusse, 2024. "Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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