PT  - JOURNAL ARTICLE
AU  - Sandra Markovic-Mueller
AU  - Edward Stuttfeld
AU  - Mayanka Asthana
AU  - Tobias Weinert
AU  - Spencer Bliven
AU  - Kenneth N. Goldie
AU  - Kaisa Kisko
AU  - Guido Capitani
AU  - Kurt Ballmer-Hofer
TI  - Structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A
AID  - 10.1101/102822
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 102822
4099  - http://biorxiv.org/content/early/2017/01/24/102822.short
4100  - http://biorxiv.org/content/early/2017/01/24/102822.full
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.