Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations
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...
| Main Authors: | , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2017-04-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/22175 |
| _version_ | 1828166601666461696 |
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| author | Antonija Kuzmanic Ludovico Sutto Giorgio Saladino Angel R Nebreda Francesco L Gervasio Modesto Orozco |
| author_facet | Antonija Kuzmanic Ludovico Sutto Giorgio Saladino Angel R Nebreda Francesco L Gervasio Modesto Orozco |
| author_sort | Antonija Kuzmanic |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T02:04:01Z |
| format | Article |
| id | doaj.art-c79167d437ac42e5abc1ec4d6f61c530 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T02:04:01Z |
| publishDate | 2017-04-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-c79167d437ac42e5abc1ec4d6f61c5302022-12-22T03:52:36ZengeLife Sciences Publications LtdeLife2050-084X2017-04-01610.7554/eLife.22175Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulationsAntonija Kuzmanic0https://orcid.org/0000-0003-2815-5605Ludovico Sutto1https://orcid.org/0000-0002-4084-8562Giorgio Saladino2https://orcid.org/0000-0002-3234-5762Angel R Nebreda3https://orcid.org/0000-0002-7631-4060Francesco L Gervasio4https://orcid.org/0000-0003-4831-5039Modesto Orozco5https://orcid.org/0000-0002-8608-3278Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, SpainDepartment of Chemistry, University College London, London, United KingdomDepartment of Chemistry, University College London, London, United KingdomInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, SpainDepartment of Chemistry, University College London, London, United KingdomInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain; Joint BSC-CRG-IRB Program in Computational Biology, Barcelona, Spain; Department of Biochemistry, University of Barcelona, Barcelona, Spainp38α 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.https://elifesciences.org/articles/22175molecular dynamicsmetadynamicsphosphorylationkinasesp38 kinaseallostery |
| spellingShingle | Antonija Kuzmanic Ludovico Sutto Giorgio Saladino Angel R Nebreda Francesco L Gervasio Modesto Orozco Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations eLife molecular dynamics metadynamics phosphorylation kinases p38 kinase allostery |
| title | Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations |
| title_full | Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations |
| title_fullStr | Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations |
| title_full_unstemmed | Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations |
| title_short | Changes in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations |
| title_sort | changes in the free energy landscape of p38α map kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations |
| topic | molecular dynamics metadynamics phosphorylation kinases p38 kinase allostery |
| url | https://elifesciences.org/articles/22175 |
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