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

TitleChanges in the free-energy landscape of p38α MAP kinase through its canonical activation and binding events as studied by enhanced molecular dynamics simulations
Publication TypeJournal Article
Year of Publication2017
AuthorsKuzmanic, Antonija, Sutto Ludovico, Saladino Giorgio, Nebreda Angel R., Gervasio Francesco L., and Orozco Modesto
Secondary AuthorsShan, Yibing
JournaleLife
Volume6
Paginatione22175
Date Published04/2017
ISBN Number2050-084X
Keywordsallostery, kinases, metadynamics, molecular dynamics, p38 kinase, phosphorylation
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.

URLhttps://dx.doi.org/10.7554/eLife.22175
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