title: A dynamically coupled allosteric network underlies binding cooperativity in Src kinase.
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.
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Zachariah H
authors.initials: ZH
authors.lastname: Foda
authors.affiliation: D. E. Shaw Research, New York, New York 10036, USA.
authors.forename: Yibing
authors.initials: Y
authors.lastname: Shan
authors.affiliation: D. E. Shaw Research, New York, New York 10036, USA.
authors.forename: Eric T
authors.initials: ET
authors.lastname: Kim
authors.affiliation: 1] D. E. Shaw Research, New York, New York 10036, USA [2] Department of Biochemistry and Molecular Biophysics, Center for Computational Biology and Bioinformatics, Columbia University, New York, New York 10032, USA.
authors.forename: David E
authors.initials: DE
authors.lastname: Shaw
authors.affiliation: Department of Pharmacological Sciences, Stony Brook University, Stony Brook, New York 11794, USA.
authors.forename: Markus A
authors.initials: MA
authors.lastname: Seeliger
mesh_terms: D006801:Humans; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D017433:Protein Structure, Secondary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D011505:Protein-Tyrosine Kinases; D019061:src-Family Kinases