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Structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A

Sandra Markovic-Mueller, Edward Stuttfeld, Mayanka Asthana, View ORCID ProfileTobias Weinert, View ORCID ProfileSpencer Bliven, Kenneth N. Goldie, Kaisa Kisko, Guido Capitani, View ORCID ProfileKurt Ballmer-Hofer
doi: https://doi.org/10.1101/102822
Sandra Markovic-Mueller
1Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen PSI, Switzerland
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Edward Stuttfeld
2Biozentrum, University of Basel, Basel, Switzerland
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Mayanka Asthana
1Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen PSI, Switzerland
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Tobias Weinert
1Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen PSI, Switzerland
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  • ORCID record for Tobias Weinert
Spencer Bliven
1Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen PSI, Switzerland
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Kenneth N. Goldie
3Center for Cellular Imaging and Nano Analytics (C-CINA), Biozentrum, University of Basel, Basel, Switzerland
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Kaisa Kisko
1Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen PSI, Switzerland
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Guido Capitani
1Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen PSI, Switzerland
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Kurt Ballmer-Hofer
1Paul Scherrer Institute, Laboratory of Biomolecular Research, 5232 Villigen PSI, Switzerland
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  • ORCID record for Kurt Ballmer-Hofer
  • For correspondence: kurt.ballmerhofer@unibas.ch
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SUMMARY

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.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license.
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Posted January 24, 2017.
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Structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A
Sandra Markovic-Mueller, Edward Stuttfeld, Mayanka Asthana, Tobias Weinert, Spencer Bliven, Kenneth N. Goldie, Kaisa Kisko, Guido Capitani, Kurt Ballmer-Hofer
bioRxiv 102822; doi: https://doi.org/10.1101/102822
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Structure of the full-length VEGFR-1 extracellular domain in complex with VEGF-A
Sandra Markovic-Mueller, Edward Stuttfeld, Mayanka Asthana, Tobias Weinert, Spencer Bliven, Kenneth N. Goldie, Kaisa Kisko, Guido Capitani, Kurt Ballmer-Hofer
bioRxiv 102822; doi: https://doi.org/10.1101/102822

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