A dynamically coupled allosteric network underlies binding cooperativity in Src kinase

Zachariah H. Foda, Yibing Shan (), Eric T. Kim, David E. Shaw () and Markus A. Seeliger ()
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Zachariah H. Foda: Stony Brook University
Yibing Shan: D. E. Shaw Research
Eric T. Kim: D. E. Shaw Research
David E. Shaw: D. E. Shaw Research
Markus A. Seeliger: Stony Brook University

Nature Communications, 2015, vol. 6, issue 1, 1-10

Abstract: Abstract Protein tyrosine kinases are attractive drug targets because many human diseases are associated with the deregulation of kinase activity. However, how the catalytic kinase domain integrates different signals and switches from an active to an inactive conformation remains incompletely understood. Here we identify an allosteric network of dynamically coupled amino acids in Src kinase that connects regulatory sites to the ATP- and substrate-binding sites. Surprisingly, reactants (ATP and peptide substrates) bind with negative cooperativity to Src kinase while products (ADP and phosphopeptide) bind with positive cooperativity. We confirm the molecular details of the signal relay through the allosteric network by biochemical studies. Experiments on two additional protein tyrosine kinases indicate that the allosteric network may be largely conserved among these enzymes. Our work provides new insights into the regulation of protein tyrosine kinases and establishes a potential conduit by which resistance mutations to ATP-competitive kinase inhibitors can affect their activity.

Date: 2015
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DOI: 10.1038/ncomms6939

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