Structure and autoregulation of the insulin-like growth factor 1 receptor kinase

The insulin-like growth factor I (IGF1) receptor is closely related to the insulin receptor. However, the unique biological functions of IGF1 receptor make it a target for therapeutic intervention in human cancer. Using its i solated tyrosine kinase domain, we show that the IGF1 receptor is regulated by intermolecular autophosphorylation at three sites within the kinase act ivation loop. Steady-state kinetic analyses of the isolated phosphorylated forms of the IGF1 receptor kinase (IGF1RK) reveal that each autophosphoryla tion event increases enzyme turnover number and decreases K-m for ATP and p eptide. We have determined the 2.1 Angstrom -resolution crystal structure o f the tris-phosphorylated form of IGF1RK in complex with an ATP analog and a specific peptide substrate. The structure of IGF1RK reveals how the enzym e recognizes peptides containing hydrophobic residues at the P+1 and P+3 po sitions and how autophosphorylation stabilizes the activation loop in a con formation that facilitates catalysis. Although the nucleotide binding cleft is conserved between IGF1RK and the insulin receptor kinase, sequence diff erences in the nearby interlobe linker could potentially be exploited for a nticancer drug design.