Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil

New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myos...

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Autores principales: Hashem, Shaima, Tiberti, Matteo, Fornili, Arianna
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690683/
https://www.ncbi.nlm.nih.gov/pubmed/29108014
http://dx.doi.org/10.1371/journal.pcbi.1005826
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author Hashem, Shaima
Tiberti, Matteo
Fornili, Arianna
author_facet Hashem, Shaima
Tiberti, Matteo
Fornili, Arianna
author_sort Hashem, Shaima
collection PubMed
description New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations.
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spelling pubmed-56906832017-11-29 Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil Hashem, Shaima Tiberti, Matteo Fornili, Arianna PLoS Comput Biol Research Article New promising avenues for the pharmacological treatment of skeletal and heart muscle diseases rely on direct sarcomeric modulators, which are molecules that can directly bind to sarcomeric proteins and either inhibit or enhance their activity. A recent breakthrough has been the discovery of the myosin activator omecamtiv mecarbil (OM), which has been shown to increase the power output of the cardiac muscle and is currently in clinical trials for the treatment of heart failure. While the overall effect of OM on the mechano-chemical cycle of myosin is to increase the fraction of myosin molecules in the sarcomere that are strongly bound to actin, the molecular basis of its action is still not completely clear. We present here a Molecular Dynamics study of the motor domain of human cardiac myosin bound to OM, where the effects of the drug on the dynamical properties of the protein are investigated for the first time with atomistic resolution. We found that OM has a double effect on myosin dynamics, inducing a) an increased coupling of the motions of the converter and lever arm subdomains to the rest of the protein and b) a rewiring of the network of dynamic correlations, which produces preferential communication pathways between the OM binding site and distant functional regions. The location of the residues responsible for these effects suggests possible strategies for the future development of improved drugs and the targeting of specific cardiomyopathy-related mutations. Public Library of Science 2017-11-06 /pmc/articles/PMC5690683/ /pubmed/29108014 http://dx.doi.org/10.1371/journal.pcbi.1005826 Text en © 2017 Hashem et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Hashem, Shaima
Tiberti, Matteo
Fornili, Arianna
Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
title Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
title_full Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
title_fullStr Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
title_full_unstemmed Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
title_short Allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
title_sort allosteric modulation of cardiac myosin dynamics by omecamtiv mecarbil
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5690683/
https://www.ncbi.nlm.nih.gov/pubmed/29108014
http://dx.doi.org/10.1371/journal.pcbi.1005826
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