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

作者: Michele A McTigue , John A Wickersham , Chris Pinko , Richard E Showalter , Camran V Parast

DOI: 10.1016/S0969-2126(99)80042-2

关键词:

摘要: Abstract 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 surface of vascular cells. VEGFRs are receptor tyrosine kinases that, like platelet-derived (PDGFRs), contain a large insert within kinase domain. Results: We report here generation, kinetic characterization, 2.4 A crystal structure catalytic domain VEGF 2 (VEGFR2). This protein construct, which lacks 50 central residues 68-residue (KID), has comparable activity constructs containing entire KID. The structure, determined an unliganded phosphorylated state, reveals overall fold residue positions similar those observed tyrosine-kinase structures. activation loop, autophosphorylated Y1059 prior crystallization, mostly disordered; however, portion it occupies position inhibitory substrate binding. ends KID form β -like not known structures, that packs near C terminus. Conclusions: majority VEGFR2 necessary for activity. unique may also occur PDGFR family members serve properly orient signal transduction. provides target design selective anti-angiogenic therapeutic agents.

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