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 indica

SUBMITTER: Foda ZH 

PROVIDER: S-EPMC4300553 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature