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

摘要: The insulin-like growth factor 1 (IGF1) receptor is closely related to the insulin receptor. However, unique biological functions of IGF1 make it a target for therapeutic intervention in human cancer. Using its isolated tyrosine kinase domain, we show that regulated by intermolecular autophosphorylation at three sites within activation loop. Steady-state kinetic analyses phosphorylated forms (IGF1RK) reveal each event increases enzyme turnover number and decreases Km ATP peptide. We have determined 2.1 A-resolution crystal structure tris-phosphorylated form IGF1RK complex with an analog specific peptide substrate. reveals how recognizes peptides containing hydrophobic residues P+1 P+3 positions stabilizes loop conformation facilitates catalysis. Although nucleotide binding cleft conserved between kinase, sequence differences nearby interlobe linker could potentially be exploited anticancer drug design.