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Mechanistic and structural basis for activation of cardiac myosin force production by omecamtiv mecarbil

Author

Listed:
  • Vicente J. Planelles-Herrero

    (PSL Research University, CNRS
    Sorbonne Universités, IFD)

  • James J. Hartman

    (Cytokinetics, Inc.)

  • Julien Robert-Paganin

    (PSL Research University, CNRS)

  • Fady I. Malik

    (Cytokinetics, Inc.)

  • Anne Houdusse

    (PSL Research University, CNRS)

Abstract

Omecamtiv mecarbil is a selective, small-molecule activator of cardiac myosin that is being developed as a potential treatment for heart failure with reduced ejection fraction. Here we determine the crystal structure of cardiac myosin in the pre-powerstroke state, the most relevant state suggested by kinetic studies, both with (2.45 Å) and without (3.10 Å) omecamtiv mecarbil bound. Omecamtiv mecarbil does not change the motor mechanism nor does it influence myosin structure. Instead, omecamtiv mecarbil binds to an allosteric site that stabilizes the lever arm in a primed position resulting in accumulation of cardiac myosin in the primed state prior to onset of cardiac contraction, thus increasing the number of heads that can bind to the actin filament and undergo a powerstroke once the cardiac cycle starts. The mechanism of action of omecamtiv mecarbil also provides insights into uncovering how force is generated by molecular motors.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00176-5
    DOI: 10.1038/s41467-017-00176-5
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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.
    2. Alessandro Grinzato & Daniel Auguin & Carlos Kikuti & Neha Nandwani & Dihia Moussaoui & Divya Pathak & Eaazhisai Kandiah & Kathleen M. Ruppel & James A. Spudich & Anne Houdusse & Julien Robert-Paganin, 2023. "Cryo-EM structure of the folded-back state of human β-cardiac myosin," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Shaima Hashem & Matteo Tiberti & Arianna Fornili, 2017. "Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil," PLOS Computational Biology, Public Library of Science, vol. 13(11), pages 1-26, November.
    4. 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.
    5. Luisa Moretto & Marko Ušaj & Oleg Matusovsky & Dilson E. Rassier & Ran Friedman & Alf Månsson, 2022. "Multistep orthophosphate release tunes actomyosin energy transduction," Nature Communications, Nature, vol. 13(1), pages 1-18, December.

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