2XV7

Crystal structure of vascular endothelial growth factor D

Summary for 2XV7

• Entry DOI: 10.2210/pdb2xv7/pdb
• Descriptor: VASCULAR ENDOTHELIAL GROWTH FACTOR D, beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, alpha-D-mannopyranose, ... (4 entities in total)
• Functional Keywords: angiogenesis, lymphangiogenesis, hormone
• Biological source: HOMO SAPIENS (HUMAN)
• Total number of polymer chains: 1
• Total formula weight: 14095.65

Authors

Leppanen, V.-M.,Jeltsch, M.,Anisimov, A.,Tvorogov, D.,Aho, K.,Kalkkinen, N.,Toivanen, P.,Yla-Herttuala, S.,Ballmer-Hofer, K.,Alitalo, K. (deposition date: 2010-10-23, release date: 2011-01-12, Last modification date: 2024-11-13)

Primary citation

Leppanen, V.M.,Jeltsch, M.,Anisimov, A.,Tvorogov, D.,Aho, K.,Kalkkinen, N.,Toivanen, P.,Yla-Herttuala, S.,Ballmer-Hofer, K.,Alitalo, K.
Structural Determinants of Vascular Endothelial Growth Factor-D - Receptor Binding and Specificity.
Blood, 117:1507-, 2011

PubMed Abstract: Vascular endothelial growth factors (VEGFs) and their tyrosine kinase receptors (VEGFR-1-3) are central mediators of angiogenesis and lymphangiogenesis. VEGFR-3 ligands VEGF-C and VEGF-D are produced as precursor proteins with long N- and C-terminal propeptides and show enhanced VEGFR-2 and VEGFR-3 binding on proteolytic removal of the propeptides. Two different proteolytic cleavage sites have been reported in the VEGF-D N-terminus. We report here the crystal structure of the human VEGF-D Cys117Ala mutant at 2.9 Å resolution. Comparison of the VEGF-D and VEGF-C structures shows similar extended N-terminal helices, conserved overall folds, and VEGFR-2 interacting residues. Consistent with this, the affinity and the thermodynamic parameters for VEGFR-2 binding are very similar. In comparison with VEGF-C structures, however, the VEGF-D N-terminal helix was extended by 2 more turns because of a better resolution. Both receptor binding and functional assays of N-terminally truncated VEGF-D polypeptides indicated that the residues between the reported proteolytic cleavage sites are important for VEGF-D binding and activation of VEGFR-3, but not of VEGFR-2. Thus, we define here a VEGFR-2-specific form of VEGF-D that is angiogenic but not lymphangiogenic. These results provide important new insights into VEGF-D structure and function.

PubMed: 21148085
DOI: 10.1182/BLOOD-2010-08-301549

Experimental method

X-RAY DIFFRACTION (2.9 Å)