Crystal structure at 1.7 A resolution of VEGF in complex with domain 2 of the Flt-1 receptor.
Vascular endothelial growth factor (VEGF) is a homodimeric hormone that induces proliferation of endothelial cells through binding to the kinase domain receptor and the Fms-like tyrosine kinase receptor (Flt-1), the extracellular portions of which consist of seven immunoglobulin domains. We show that the second and third domains of Flt-1 are necessary and sufficient for binding VEGF with near-native affinity, and that domain 2 alone binds only 60-fold less tightly than wild-type. The crystal structure of the complex between VEGF and the second domain of Flt-1 shows domain 2 in a predominantly hydrophobic interaction with the "poles" of the VEGF dimer. Based on this structure and on mutational data, we present a model of VEGF bound to the first four domains of Flt-1.
Wiesmann
C
C
Genentech, Inc., Department of Protein Engineering, South San Francisco, California 94080, USA.
Fuh
G
G
Christinger
H W
HW
Eigenbrot
C
C
Wells
J A
JA
de Vos
A M
AM
D002478:Cells, Cultured; D003461:Crystallography; D016228:Endothelial Growth Factors / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008222:Lymphokines / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D016296:Mutagenesis; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D008222:Lymphokines; D010446:Peptide Fragments; D011518:Proto-Oncogene Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D020794:Receptor Protein-Tyrosine Kinases; D017479:Receptors, Platelet-Derived Growth Factor; D040281:Vascular Endothelial Growth Factor Receptor-1