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

Autor:	Auguin D; Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University, 26 rue d'Ulm, 75258 Paris cedex 05, France.; Laboratoire de Biologie des Ligneux et des Grandes Cultures, Université d'Orléans, UPRES EA 1207, INRAE- USC1328, F-45067 Orléans, France., Robert-Paganin J; Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University, 26 rue d'Ulm, 75258 Paris cedex 05, France., Réty S; Laboratoire de Biologie et Modélisation de la Cellule, ENS de Lyon, University Claude Bernard, CNRS UMR 5239, INSERM U1210, 46 Allée d'Italie Site Jacques Monod, F-69007 Lyon, France., Kikuti C; Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University, 26 rue d'Ulm, 75258 Paris cedex 05, France., David A; Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University, 26 rue d'Ulm, 75258 Paris cedex 05, France., Theumer G; Faculty of Chemistry, TU Dresden, Bergstraße 66, 01069 Dresden, Germany., Schmidt AW; Faculty of Chemistry, TU Dresden, Bergstraße 66, 01069 Dresden, Germany., Knölker HJ; Faculty of Chemistry, TU Dresden, Bergstraße 66, 01069 Dresden, Germany., Houdusse A; Structural Motility, UMR 144 CNRS/Curie Institute, PSL Research University, 26 rue d'Ulm, 75258 Paris cedex 05, France.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 15. Date of Electronic Publication: 2023 Nov 15.
DOI:	10.1101/2023.11.15.567213
Abstrakt:	Inherited cardiomyopathies are amongst the most 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. Two of these molecules that produce antagonistic effects on cardiac contractility have completed clinical phase 3 trials: the activator Omecamtiv mecarbil and the inhibitor Mavacamten . In this work, 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 atoms molecular dynamics simulations reveal how these molecules can have antagonistic impact on the allostery of the motor by comparing β-cardiac myosin in the apo form or bound to Omecamtiv mecarbil or Mavacamten . Altogether, our results provide the framework for rational drug development for the purpose of personalized medicine.
Databáze:	MEDLINE
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