3V2A

VEGFR-2/VEGF-A COMPLEX STRUCTURE

Summary for 3V2A

• Entry DOI: 10.2210/pdb3v2a/pdb
• Related: 2GNN 2X1W 2X1X 3V6B
• Descriptor: Vascular endothelial growth factor receptor 2, Vascular endothelial growth factor A (2 entities in total)
• Functional Keywords: ig-homology domain, vegfr-2, growth factor receptor, vegf ligand, hormone-signaling protein complex, angiogenesis, membrane, vegf-a, hormone/signaling protein
• Biological source: Homo sapiens (human); More
• Cellular location: Cell junction . Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted . Isoform 3: Secreted: P35968; Secreted : P15692
• Total number of polymer chains: 2
• Total formula weight: 102109.06

Authors

Brozzo, M.S.,Leppanen, V.-M.,Winkler, F.K.,Ballmer-Hofer, K. (deposition date: 2011-12-12, release date: 2012-01-18, Last modification date: 2024-11-20)

Primary citation

Brozzo, M.S.,Bjelic, S.,Kisko, K.,Schleier, T.,Leppanen, V.M.,Alitalo, K.,Winkler, F.K.,Ballmer-Hofer, K.
Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization.
Blood, 119:1781-1788, 2012

PubMed Abstract: 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.

PubMed: 22207738
DOI: 10.1182/blood-2011-11-390922

Experimental method

X-RAY DIFFRACTION (3.204 Å)