VEGFs activate 3 receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3, promoting angiogenic and lymphangiogenic signaling. The extracellular receptor domain (ECD) consists of 7 Ig-homology domains; domains 2 and 3 (D23) represent the ligand-binding domain, whereas the function of D4-7 is unclear. Ligand binding promotes receptor dimerization and instigates transmembrane signaling and receptor kinase activation. In the present study, isothermal titration calorimetry showed that the Gibbs free energy of VEGF-A, VEGF-C, or VEGF-E binding to D23 or the full-length ECD of VEGFR-2 is dominated by favorable entropic contribution with enthalpic penalty. The free energy of VEGF binding to the ECD is 1.0-1.7 kcal/mol less favorable than for binding to D23. A model of the VEGF-E/VEGFR-2 ECD complex derived from small-angle scattering data provided evidence for homotypic interactions in D4-7. We also solved the crystal structures of complexes between VEGF-A or VEGF-E with D23, which revealed comparable binding surfaces and similar interactions between the ligands and the receptor, but showed variation in D23 twist angles. The energetically unfavorable homotypic interactions in D4-7 may be required for re-orientation of receptor monomers, and this mechanism might prevent ligand-independent activation of VEGFR-2 to evade the deleterious consequences for blood and lymph vessel homeostasis arising from inappropriate receptor activation.
PDB ID: 3V2ADownload
MMDB ID: 96568
PDB Deposition Date: 2011/12/12
Updated in MMDB: 2017/11
Experimental Method:
x-ray diffraction
Resolution: 3.204  Å
Source Organism:
Similar Structures:
Biological Unit for 3V2A: tetrameric; determined by author and by software (PISA)
Molecular Components in 3V2A
Label Count Molecule
Proteins (4 molecules)
Vascular Endothelial Growth Factor Receptor 2(Gene symbol: KDR)
Molecule annotation
Vascular Endothelial Growth Factor a(Gene symbol: VEGFA)
Molecule annotation
* Click molecule labels to explore molecular sequence information.

Citing MMDB