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Sci Rep. 2016 Apr 11;6:24235. doi: 10.1038/srep24235.

An Allosteric Cross-Talk Between the Activation Loop and the ATP Binding Site Regulates the Activation of Src Kinase.

Author information

Department of Chemistry, University College London, London WC1E 6BT, United Kingdom.
Research Institute of Structural and Molecular Biology, University College London, London WC1E 6BT, United Kingdom.
Center of Technological Development in Health, Oswaldo Cruz Foundation (Fiocruz), Rio de Janeiro, Brazil.
Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), 28029, Madrid, Spain.
Centre de RMN à Très Hauts Champs, Institut de Sciences Analytiques, (CNRS/ENS Lyon/Universitè CB Lyon 1), 69100 Villeurbanne, France.


Phosphorylation of the activation loop is a fundamental step in the activation of most protein kinases. In the case of the Src tyrosine kinase, a prototypical kinase due to its role in cancer and its historic importance, phosphorylation of tyrosine 416 in the activation loop is known to rigidify the structure and contribute to the switch from the inactive to a fully active form. However, whether or not phosphorylation is able per-se to induce a fully active conformation, that efficiently binds ATP and phosphorylates the substrate, is less clear. Here we employ a combination of solution NMR and enhanced-sampling molecular dynamics simulations to fully map the effects of phosphorylation and ATP/ADP cofactor loading on the conformational landscape of Src tyrosine kinase. We find that both phosphorylation and cofactor binding are needed to induce a fully active conformation. What is more, we find a complex interplay between the A-loop and the hinge motion where the phosphorylation of the activation-loop has a significant allosteric effect on the dynamics of the C-lobe.

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