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Vascular endothelial growth factor: crystal structure and functional mapping of the kinase domain receptor binding
Y A Muller1, B Li, H W Christinger
1Genentech, Inc., Department of Protein Engineering, 460 Point San Bruno Boulevard, South San Francisco, CA 94080, USA.
Abstract:
Vascular endothelial growth factor (VEGF) is a homodimeric member of the cystine knot family of growth factors, with limited sequence homology to platelet-derived growth factor (PDGF) and transforming growth factor beta2 (TGF-beta). We have determined its crystal structure at a resolution of 2.5 A, and identified its kinase domain receptor (KDR) binding site using mutational analysis. Overall, the VEGF monomer resembles that of PDGF, but its N-terminal segment is helical rather than extended. The dimerization mode of VEGF is similar to that of PDGF and very different from that of TGF-beta. Mutational analysis of VEGF reveals that symmetrical binding sites for KDR are located at each pole of the VEGF homodimer. Each site contains two functional "hot spots" composed of binding determinants presented across the subunit interface. The two most important determinants are located within the largest hot spot on a short, three-stranded sheet that is conserved in PDGF and TGF-beta. Functional analysis of the binding epitopes for two receptor-blocking antibodies reveal different binding determinants near each of the KDR binding hot spots.