In silico activation of Src tyrosine kinase reveals the molecular basis for intramolecular autophosphorylation

Journal of Molecular Graphics & Modelling
Jesús Mendieta, Federico Gago

Abstract

Structural data suggest that important hinge-bending motions of the two lobes that shape the catalytic domain of Src tyrosine kinase, together with reorganization of an alpha helix (helix C), are needed for the activation loop to adopt the catalytically competent conformation. The phosphorylation of a Tyr residue (Tyr-416) in this loop also seems to be essential for enzyme activation. However, no information is available about the dynamics of this activation process. By comparing the inactive and active forms of the catalytic domains of Src and Lck, another member of the Src family, we first identified a short stretch that can act as a hinge for the interlobe motion. The opening of the lobes was then simulated using a targeted molecular dynamics approach. The results obtained suggested that pulling the two lobes apart is not enough to induce the required conformational change in the activation loop. Rather unexpectedly, however, swinging of the lobes situated Tyr-416 in a suitable position for intramolecular autophosphorylation, and further simulation of Tyr-416-phosphorylated Src in the presence of ADP did then result in a conformational change that placed the activation loop in a position similar to that found in the active o...Continue Reading

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Citations

Jan 26, 2011·The Journal of Physical Chemistry. B·Chunli YanPengyu Ren
Feb 20, 2009·Proceedings of the National Academy of Sciences of the United States of America·Sichun YangBenoît Roux
Jul 29, 2008·The Journal of Biological Chemistry·Dominik FilippMichael Julius
Jul 3, 2007·Applied and Environmental Microbiology·Emilio Blas-GalindoJosé Berenguer
May 31, 2012·Proteome Science·Elena LópezMartin Latterich
Oct 5, 2011·Journal of Clinical Bioinformatics·Elena LópezSarbelio Rodríguez Muñoz
Apr 22, 2006·PLoS Computational Biology·Eli S GrobanMatthew P Jacobson
Jul 16, 2008·Proteins·Nilesh K Banavali, Benoît Roux
Mar 26, 2010·Archiv der Pharmazie·Matthias RabillerDaniel Rauh
Nov 26, 2004·Journal of the American Chemical Society·Fátima Rodríguez-Barrios, Federico Gago

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