2X1X: Crystal Structure Of Vegf-c In Complex With Domains 2 And 3 Of Vegfr2 In A Tetragonal Crystal Form

Citation:
Abstract
Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel formation through activation of three receptor tyrosine kinases, VEGFR-1, -2, and -3. The extracellular domain of VEGF receptors consists of seven immunoglobulin homology domains, which, upon ligand binding, promote receptor dimerization. Dimerization initiates transmembrane signaling, which activates the intracellular tyrosine kinase domain of the receptor. VEGF-C stimulates lymphangiogenesis and contributes to pathological angiogenesis via VEGFR-3. However, proteolytically processed VEGF-C also stimulates VEGFR-2, the predominant transducer of signals required for physiological and pathological angiogenesis. Here we present the crystal structure of VEGF-C bound to the VEGFR-2 high-affinity-binding site, which consists of immunoglobulin homology domains D2 and D3. This structure reveals a symmetrical 22 complex, in which left-handed twisted receptor domains wrap around the 2-fold axis of VEGF-C. In the VEGFs, receptor specificity is determined by an N-terminal alpha helix and three peptide loops. Our structure shows that two of these loops in VEGF-C bind to VEGFR-2 subdomains D2 and D3, while one interacts primarily with D3. Additionally, the N-terminal helix of VEGF-C interacts with D2, and the groove separating the two VEGF-C monomers binds to the D2/D3 linker. VEGF-C, unlike VEGF-A, does not bind VEGFR-1. We therefore created VEGFR-1/VEGFR-2 chimeric proteins to further study receptor specificity. This biochemical analysis, together with our structural data, defined VEGFR-2 residues critical for the binding of VEGF-A and VEGF-C. Our results provide significant insights into the structural features that determine the high affinity and specificity of VEGF/VEGFR interactions.
PDB ID: 2X1XDownload
MMDB ID: 79888
PDB Deposition Date: 2010/1/8
Updated in MMDB: 2011/08
Experimental Method:
x-ray diffraction
Resolution: 3.1  Å
Source Organism:
Similar Structures:
Biological Unit for 2X1X: tetrameric; determined by author and by software (PISA)
Molecular Components in 2X1X
Label Count Molecule
Proteins (4 molecules)
2
Vascular Endothelial Growth Factor C(Gene symbol: VEGFC)
Molecule annotation
2
Vascular Endothelial Growth Factor Receptor 2(Gene symbol: KDR)
Molecule annotation
Chemicals (18 molecules)
1
16
2
2
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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