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

Francesco L Gervasio¹  Ludovico Sutto²  Giorgio Saladino²  Modesto Orozco²  Angel R Nebreda³  Antonija Kuzmanic³ 

[1] Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain;Department of Chemistry, University College London, London, United Kingdom;Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain;

关键词: molecular dynamics;    metadynamics;    phosphorylation;    kinases;    p38 kinase;    allostery;   

DOI  :  10.7554/eLife.22175

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown