Unravelling the effect of the E545K mutation on PI3Kα kinase

PI3Kα controls several cellular processes and its aberrant signalling is implicated in tumorigenesis. One of its hotspot mutations, E545K, increases PI3Kα lipid kinase activity, but its mode of action is only partially understood. Here, we perform biased and unbiased molecular dynamics simulations o...

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Detalles Bibliográficos
Autores principales: Galdadas, Ioannis, Gervasio, Francesco Luigi, Cournia, Zoe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2020
Materias:
Chemistry
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493679/
https://www.ncbi.nlm.nih.gov/pubmed/34703536
http://dx.doi.org/10.1039/c9sc05903b
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author Galdadas, Ioannis
Gervasio, Francesco Luigi
Cournia, Zoe
author_facet Galdadas, Ioannis
Gervasio, Francesco Luigi
Cournia, Zoe
author_sort Galdadas, Ioannis
collection PubMed
description PI3Kα controls several cellular processes and its aberrant signalling is implicated in tumorigenesis. One of its hotspot mutations, E545K, increases PI3Kα lipid kinase activity, but its mode of action is only partially understood. Here, we perform biased and unbiased molecular dynamics simulations of PI3Kα and uncover, for the first time, the free energy landscape of the E545K PI3Kα mutant. We reveal the mechanism by which E545K leads to PI3Kα activation in atomic-level detail, which is considerably more complex than previously thought.
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spelling pubmed-84936792021-10-25 Unravelling the effect of the E545K mutation on PI3Kα kinase Galdadas, Ioannis Gervasio, Francesco Luigi Cournia, Zoe Chem Sci Chemistry PI3Kα controls several cellular processes and its aberrant signalling is implicated in tumorigenesis. One of its hotspot mutations, E545K, increases PI3Kα lipid kinase activity, but its mode of action is only partially understood. Here, we perform biased and unbiased molecular dynamics simulations of PI3Kα and uncover, for the first time, the free energy landscape of the E545K PI3Kα mutant. We reveal the mechanism by which E545K leads to PI3Kα activation in atomic-level detail, which is considerably more complex than previously thought. The Royal Society of Chemistry 2020-02-26 /pmc/articles/PMC8493679/ /pubmed/34703536 http://dx.doi.org/10.1039/c9sc05903b Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Galdadas, Ioannis
Gervasio, Francesco Luigi
Cournia, Zoe
Unravelling the effect of the E545K mutation on PI3Kα kinase
title Unravelling the effect of the E545K mutation on PI3Kα kinase
title_full Unravelling the effect of the E545K mutation on PI3Kα kinase
title_fullStr Unravelling the effect of the E545K mutation on PI3Kα kinase
title_full_unstemmed Unravelling the effect of the E545K mutation on PI3Kα kinase
title_short Unravelling the effect of the E545K mutation on PI3Kα kinase
title_sort unravelling the effect of the e545k mutation on pi3kα kinase
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8493679/
https://www.ncbi.nlm.nih.gov/pubmed/34703536
http://dx.doi.org/10.1039/c9sc05903b
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