8qyr
Beta-cardiac myosin motor domain in the pre-powerstroke state complexed to MavacamtenBeta-cardiac myosin motor domain in the pre-powerstroke state complexed to Mavacamten
Structural highlights
FunctionMYH7_BOVIN Muscle contraction. Publication Abstract from PubMedInherited 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 beta-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 beta-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. Omecamtiv mecarbil and Mavacamten target the same myosin pocket despite antagonistic effects in heart contraction.,Auguin D, Robert-Paganin J, Rety S, Kikuti C, David A, Theumer G, Schmidt AW, Knolker HJ, Houdusse A bioRxiv. 2023 Nov 15:2023.11.15.567213. doi: 10.1101/2023.11.15.567213. Preprint. PMID:38014327[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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