2GNN

Crystal Structure of the Orf Virus NZ2 Variant of VEGF-E

Summary for 2GNN

• Entry DOI: 10.2210/pdb2gnn/pdb
• Related: 1FZV 1VPF 1WQ8 1WQ9
• Descriptor: Vascular endothelial growth factor homolog, CHLORIDE ION, SULFATE ION, ... (8 entities in total)
• Functional Keywords: vegf, orf, s-sad, hormone-growth factor complex, hormone/growth factor
• Biological source: Orf virus (strain NZ2)
• Cellular location: Secreted : P52584
• Total number of polymer chains: 4
• Total formula weight: 59174.71

Authors

Prota, A.E.,Pieren, M.,Wagner, A.,Kostrewa, D.,Winkler, F.K.,Ballmer-Hofer, K. (deposition date: 2006-04-10, release date: 2006-05-09, Last modification date: 2025-11-12)

Primary citation

Pieren, M.,Prota, A.E.,Ruch, C.,Kostrewa, D.,Wagner, A.,Biedermann, K.,Winkler, F.K.,Ballmer-Hofer, K.
Crystal structure of the Orf virus NZ2 variant of vascular endothelial growth factor-E. Implications for receptor specificity.
J.Biol.Chem., 281:19578-19587, 2006

PubMed Abstract: Mammalian vascular endothelial growth factors constitute a family of polypeptides, vascular endothelial growth factor (VEGF)-A, -B, -C, -D and placenta growth factor (PlGF), that regulate blood and lymphatic vessel development. VEGFs bind to three types of receptor tyrosine kinases, VEGF receptors 1, 2, and 3, that are predominantly expressed on endothelial and some hematopoietic cells. Pox viruses of the Orf family encode highly related proteins called VEGF-E that show only 25-35% amino acid identity with VEGF-A but bind with comparable affinity to VEGFR-2. The crystal structure of VEGF-E NZ2 described here reveals high similarity to the known structural homologs VEGF-A, PlGF, and the snake venoms Vammin and VR-1, which are all homodimers and contain the characteristic cysteine knot motif. Distinct conformational differences are observed in loop L1 and particularly in L3, which contains a highly flexible GS-rich motif that differs from all other structural homologs. Based on our structure, we created chimeric proteins by exchanging selected segments in L1 and L3 with the corresponding sequences from PlGF. Single loop mutants did not bind to either receptor, whereas a VEGF-E mutant in which both L1 and L3 were replaced gained affinity for VEGFR-1, illustrating the possibility to engineer receptor-specific chimeric VEGF molecules. In addition, changing arginine 46 to isoleucine in L1 significantly increased the affinity of VEGF-E for both VEGF receptors.

PubMed: 16672228
DOI: 10.1074/jbc.M601842200

Experimental method

X-RAY DIFFRACTION (2.3 Å)