Structural insights into the binding of vascular endothelial growth factor-B by VEGFR-1(D2): recognition and specificity.
The formation of blood vessels (angiogenesis) is a highly orchestrated sequence of events involving crucial receptor-ligand interactions. Angiogenesis is critical for physiological processes such as development, wound healing, reproduction, tissue regeneration, and remodeling. It also plays a major role in sustaining tumor progression and chronic inflammation. Vascular endothelial growth factor (VEGF)-B, a member of the VEGF family of angiogenic growth factors, effects blood vessel formation by binding to a tyrosine kinase receptor, VEGFR-1. There is growing evidence of the important role played by VEGF-B in physiological and pathological vasculogenesis. Development of VEGF-B antagonists, which inhibit the interaction of this molecule with its cognate receptor, would be important for the treatment of pathologies associated specifically with this growth factor. In this study, we present the crystal structure of the complex of VEGF-B with domain 2 of VEGFR-1 at 2.7 A resolution. Our analysis reveals that each molecule of the ligand engages two receptor molecules using two symmetrical binding sites. Based on these interactions, we identify the receptor-binding determinants on VEGF-B and shed light on the differences in specificity towards VEGFR-1 among the different VEGF homologs.
Iyer
Shalini
S
Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, United Kingdom.
Darley
Paula I
PI
Acharya
K Ravi
KR
D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray / Q000379:methods; D019281:Dimerization; D006801:Humans; D008024:Ligands; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009389:Neovascularization, Pathologic; D011485:Protein Binding; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry; D017386:Sequence Homology, Amino Acid; D013329:Structure-Activity Relationship; D042561:Vascular Endothelial Growth Factor B / Q000737:chemistry*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry*
D008024:Ligands; D011994:Recombinant Proteins; D042561:Vascular Endothelial Growth Factor B; D040281:Vascular Endothelial Growth Factor Receptor-1