Crystal structure of the kinase domain of human vascular endothelial growth factor receptor 2: a key enzyme in angiogenesis

Background: Angiogenesis is involved,in tumor growth, macular degeneration, retinopathy and other diseases. Vascular endothelial growth factor (VEGF) stimulates angiogenesis by binding to specific receptors (VEGFRs) on the su rface of vascular endothelial cells. VEGFRs are receptor tyrosine kinases t hat, like the platelet-derived growth factor receptors (PDGFRs), contain a large insert within the kinase domain. Results: We report here the generation, kinetic characterization, and 2.4 A ngstrom crystal structure of the catalytic kinase domain of VEGF receptor 2 (VEGFR2). This protein construct, which lacks 50 central residues of the 6 8-residue kinase insert domain (KID), has comparable kinase activity to con structs containing the entire KID. The crystal; structure, determined in an unliganded phosphorylated state, reveals an overall fold and catalytic res idue positions similar to those observed in other tyrosine-kinase structure s. The kinase activation loop, autophosphorylated on Y1059 prior to crystal lization, is mostly disordered; however, a portion of it occupies a positio n inhibitory to substrate binding. The ends of the KID form a beta-like str ucture, not observed in other known tyrosine kinase structures, that packs near to the kinase C terminus. Conclusions: The majority of the VEGFR2 KID residues are not necessary for kinase activity. The unique structure observed for the ends of the KID may also occur in other PDGFR family members and may serve to properly orient t he KID for signal transduction. This VEGFR2 kinase structure provides a tar get for design of selective anti-angiogenic therapeutic agents.