title: Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A.
abstract: Vascular endothelial growth factors (VEGFs) regulate blood and lymph vessel development upon activation of three receptor tyrosine kinases: 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 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 immunoglobulin homology 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.
authors.affiliation: Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen, Switzerland.
authors.forename: Sandra
authors.initials: S
authors.lastname: Markovic-Mueller
authors.affiliation: Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Edward
authors.initials: E
authors.lastname: Stuttfeld
authors.affiliation: Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen, Switzerland.
authors.forename: Mayanka
authors.initials: M
authors.lastname: Asthana
authors.affiliation: Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen, Switzerland.
authors.forename: Tobias
authors.initials: T
authors.lastname: Weinert
authors.affiliation: Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen, Switzerland; National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health, Bethesda, MD 20894, USA.
authors.forename: Spencer
authors.initials: S
authors.lastname: Bliven
authors.affiliation: Center for Cellular Imaging and Nano Analytics (C-CINA), Biozentrum, University of Basel, 4056 Basel, Switzerland.
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Goldie
authors.affiliation: Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen, Switzerland.
authors.forename: Kaisa
authors.initials: K
authors.lastname: Kisko
authors.affiliation: Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen, Switzerland.
authors.forename: Guido
authors.initials: G
authors.lastname: Capitani
authors.affiliation: Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen, Switzerland. Electronic address: kurt.ballmer-hofer@unibas.ch.
authors.forename: Kurt
authors.initials: K
authors.lastname: Ballmer-Hofer
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D003001:Cloning, Molecular; D018360:Crystallography, X-Ray; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D008854:Microscopy, Electron; D008958:Models, Molecular; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D000072757:Protein Conformation, beta-Strand; D054730:Protein Interaction Domains and Motifs; D055503:Protein Multimerization; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics; D042461:Vascular Endothelial Growth Factor A / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
chemical_list: D008024:Ligands; D011994:Recombinant Proteins; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D040281:Vascular Endothelial Growth Factor Receptor-1
keywords: VEGF receptor; X-ray crystallography; angiogenesis; extracellular domain; receptor tyrosine kinase; single-particle negative stain electron microscopy; small-angle X-ray scattering; vascular endothelial growth factor