Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations

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• dc.contributor.author Kuzmanic, Antonijaca
• dc.contributor.author Sutto, Ludovicoca
• dc.contributor.author Saladino, Giorgioca
• dc.contributor.author Nebreda, Ángel R.ca
• dc.contributor.author Gervasio, Francesco L.ca
• dc.contributor.author Orozco, Modestoca
• dc.date.accessioned 2018-05-25T07:40:36Z
• dc.date.available 2018-05-25T07:40:36Z
• dc.date.issued 2017
• dc.description.abstract p38α is a Ser/Thr protein kinase involved in a variety of cellular processes and pathological conditions, which makes it a promising pharmacological target. Although the activity of the enzyme is highly regulated, its molecular mechanism of activation remains largely unexplained, even after decades of research. By using state-of-the-art molecular dynamics simulations, we decipher the key elements of the complex molecular mechanism refined by evolution to allow for a fine tuning of p38α kinase activity. Our study describes for the first time the molecular effects of different regulators of the enzymatic activity, and provides an integrative picture of the activation mechanism that explains the seemingly contradictory X-ray and NMR data.
• dc.description.sponsorship AK was partly supported by the European Union Seventh Framework Programme (FP7/Marie Curie Actions/COFUND, no. 600404). FLG and GS acknowledge financial support from EPSRC (grant EP/M013898/1). ARN was supported by a grant from the European Commission (ERC, project ID: 294665). MO is an ICREA research fellow. MO acknowledges the support from two grants from the European Commission H2020 program (BioExcel project ID: 676559 and ELIXIR- Excellerate project ID: 675728) and the Spanish MINECO (BIO2015/64802-R).
• dc.format.mimetype application/pdf
• dc.identifier.citation Kuzmanic A, Sutto L, Saladino G, Nebreda AR, Gervasio FL, Orozco M. Changes in the free-energy landscape of p38alpha MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations. Elife. 2017 Apr 26;6:e22175. DOI: 10.7554/eLife.22175
• dc.identifier.doi http://dx.doi.org/10.7554/eLife.22175
• dc.identifier.issn 2050-084X
• dc.identifier.uri http://hdl.handle.net/10230/34725
• dc.language.iso eng
• dc.publisher eLifeca
• dc.relation.ispartof Elife. 2017 Apr 26;6:e22175
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/600404
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/294665
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/676559
• dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/675728
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BIO2015-64802-R
• dc.rights © 2017, Kuzmanic et al. This article is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use and redistribution provided that the original author and source are credited.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword Allostery
• dc.subject.keyword Molecular dynamics
• dc.subject.keyword P38 kinase
• dc.subject.keyword Biophysics
• dc.subject.keyword Phosphorylation
• dc.subject.keyword Structural biology
• dc.subject.keyword Metadynamics
• dc.subject.keyword Kinases
• dc.title Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulationsca
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion