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Structure of the Full-length VEGFR-1 Extracellular Domain in Complex with VEGF-A.

Markovic-Mueller S, Stuttfeld E, Asthana M, Weinert T, Bliven S, Goldie KN, Kisko K, Capitani G, Ballmer-Hofer K
Structure 25 341-352 (2017)
Cited: 54 times
EuropePMC logo PMID: 28111021

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.

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  5. Cryo-electron Microscopic Analysis of Single-Pass Transmembrane Receptors. Cai K, Zhang X, Bai XC. Chem Rev 122 13952-13988 (2022)
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  7. Extracellular Vesicles (EVs) in Tumor Diagnosis and Therapy. Tan M, Ge Y, Wang X, Wang Y, Liu Y, He F, Teng H. Technol Cancer Res Treat 22 15330338231171463 (2023)
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  9. Structural Perspectives on Extracellular Recognition and Conformational Changes of Several Type-I Transmembrane Receptors. Chataigner LMP, Leloup N, Janssen BJC. Front Mol Biosci 7 129 (2020)
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  3. VER/VEGF receptors regulate AMPA receptor surface levels and glutamatergic behavior. Luth ES, Hodul M, Rennich BJ, Riccio C, Hofer J, Markoja K, Juo P. PLoS Genet 17 e1009375 (2021)
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  7. Binding and Structural Properties of DNA Aptamers with VEGF-A-Mimic Activity. Yoshitomi T, Hayashi M, Oguro T, Kimura K, Wayama F, Furusho H, Yoshimoto K. Mol Ther Nucleic Acids 19 1145-1152 (2020)
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  11. KAI1(CD82) is a key molecule to control angiogenesis and switch angiogenic milieu to quiescent state. Lee JW, Hur J, Kwon YW, Chae CW, Choi JI, Hwang I, Yun JY, Kang JA, Choi YE, Kim YH, Lee SE, Lee C, Jo DH, Seok H, Cho BS, Baek SH, Kim HS. J Hematol Oncol 14 148 (2021)
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  13. Specific humoral response in cancer patients treated with a VEGF-specific active immunotherapy procedure within a compassionate use program. Sánchez Ramírez J, Morera Díaz Y, Bequet-Romero M, Hernández-Bernal F, Martín Bauta Y, Selman-Housein Bernal KH, de la Torre Santos AV, Pérez de la Iglesia M, Trimiño Lorenzo L, Team of Investigators of Compassionate use Program, Ayala Avila M. BMC Immunol 21 12 (2020)
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  16. The VEGF Inhibitor Soluble Fms-like Tyrosine Kinase 1 Does Not Promote AKI-to-CKD Transition. van Aanhold CCL, Koudijs A, Dijkstra KL, Wolterbeek R, Bruijn JA, van Kooten C, Baelde HJ. Int J Mol Sci 23 9660 (2022)
  17. Unraveling Determinants of Affinity Enhancement in Dimeric Aptamers for a Dimeric Protein. Manochehry S, McConnell EM, Li Y. Sci Rep 9 17824 (2019)
  18. VEGFR Recognition Interface of a Proangiogenic VEGF-Mimetic Peptide Determined In Vitro and in the Presence of Endothelial Cells by NMR Spectroscopy. Di Stasi R, Diana D, Capasso D, Di Gaetano S, De Rosa L, Celentano V, Isernia C, Fattorusso R, D'Andrea LD. Chemistry 24 11461-11466 (2018)


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