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Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite opposite effects in heart contraction

Author

Listed:
  • Daniel Auguin

    (Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144
    Université d’Orléans)

  • Julien Robert-Paganin

    (Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144)

  • Stéphane Réty

    (Université Claude Bernard Lyon 1)

  • Carlos Kikuti

    (Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144)

  • Amandine David

    (Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144)

  • Gabriele Theumer

    (TU Dresden)

  • Arndt W. Schmidt

    (TU Dresden)

  • Hans-Joachim Knölker

    (TU Dresden)

  • Anne Houdusse

    (Institut Curie, Université Paris Sciences et Lettres, Sorbonne Université, CNRS UMR144)

Abstract

Inherited cardiomyopathies are common cardiac diseases worldwide, leading in the late stage to heart failure and death. The most promising treatments against these diseases are small molecules directly modulating the force produced by β-cardiac myosin, the molecular motor driving heart contraction. Omecamtiv mecarbil and Mavacamten are two such molecules that completed phase 3 clinical trials, and the inhibitor Mavacamten is now approved by the FDA. In contrast to Mavacamten, Omecamtiv mecarbil acts as an activator of cardiac contractility. Here, we reveal by X-ray crystallography that both drugs target the same pocket and stabilize a pre-stroke structural state, with only few local differences. All-atom molecular dynamics simulations reveal how these molecules produce distinct effects in motor allostery thus impacting force production in opposite way. Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-47587-9
    DOI: 10.1038/s41467-024-47587-9
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    References listed on IDEAS

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    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. 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.
    3. 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.
    4. Michael S. Woody & Michael J. Greenberg & Bipasha Barua & Donald A. Winkelmann & Yale E. Goldman & E. Michael Ostap, 2018. "Positive cardiac inotrope omecamtiv mecarbil activates muscle despite suppressing the myosin working stroke," Nature Communications, Nature, vol. 9(1), pages 1-11, December.
    5. 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.
    6. Julien Robert-Paganin & Daniel Auguin & Anne Houdusse, 2018. "Hypertrophic cardiomyopathy disease results from disparate impairments of cardiac myosin function and auto-inhibition," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
    7. 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.
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