RT Journal Article
SR Electronic
T1 Structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 102822
DO 10.1101/102822
A1 Markovic-Mueller, Sandra
A1 Stuttfeld, Edward
A1 Asthana, Mayanka
A1 Weinert, Tobias
A1 Bliven, Spencer
A1 Goldie, Kenneth N.
A1 Kisko, Kaisa
A1 Capitani, Guido
A1 Ballmer-Hofer, Kurt
YR 2017
UL http://biorxiv.org/content/early/2017/01/24/102822.abstract
AB Vascular Endothelial Growth Factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases (RTKs), VEGFR-1, −2, and −3. Partial structures of VEGFR/VEGF complexes based on single particle electron microscopy, small angle X-ray scattering, and X-ray crystallography revealed the location of VEGF binding and domain arrangement of individual receptor subdomains. Here we describe the structure of the full-length VEGFR-1 extracellular domain (ECD) in complex with VEGF-A at 4 Å resolution. We combined X-ray crystallography, single particle electron microscopy, and molecular modeling for structure determination and validation. The structure reveals the molecular details of ligand-induced receptor dimerization, in particular of homotypic receptor interactions in Ig-domains 4, 5, and 7. Functional analyses of ligand binding and receptor activation confirm the relevance of these homotypic contacts and identify them as potential therapeutic sites to allosterically inhibit VEGFR-1 activity.