A dynamically coupled allosteric network underlies binding cooperativity in Src kinase

• Published in: Nature communications Vol. 6; no. 1; p. 5939
• Main Authors: Foda, Zachariah H., Shan, Yibing, Kim, Eric T., Shaw, David E., Seeliger, Markus A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 20.01.2015; Nature Publishing Group; Nature Pub. Group
• Subjects: 631/45/535; 631/57/2272; 82/80; 9/10; Adenosine diphosphate; Amino acids; ATP; Deregulation; Humanities and Social Sciences; Humans; Molecular Dynamics Simulation; multidisciplinary; Protein Binding; Protein Structure, Secondary; Protein-Tyrosine Kinases - chemistry; Protein-Tyrosine Kinases - genetics; Protein-Tyrosine Kinases - metabolism; Science; Science (multidisciplinary); src-Family Kinases - chemistry; src-Family Kinases - genetics; src-Family Kinases - metabolism
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms6939

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. Protein tyrosine kinases are subject to multiple regulatory mechanisms. Foda et al . show that reactants and products of the tyrosine kinase Src bind its catalytic domain with opposite cooperativity, and identify an allosteric network of dynamically coupled amino acids that underlie this behaviour.