3v6b › Citations

Thermodynamic and structural description of allosterically regulated VEGFR-2 dimerization.

Brozzo MS, Bjelić S, Kisko K, Schleier T, Leppänen VM, Alitalo K, Winkler FK, Ballmer-Hofer K
Blood 119 1781-8 (2012)
Cited: 75 times
EuropePMC logo PMID: 22207738

Abstract

VEGFs activate 3 receptor tyrosine kinases, VEGFR-1, VEGFR-2, and VEGFR-3, promoting angiogenic and lymphangiogenic signaling. The extracellular receptor domain (ECD) consists of 7 Ig-homology domains; domains 2 and 3 (D23) represent the ligand-binding domain, whereas the function of D4-7 is unclear. Ligand binding promotes receptor dimerization and instigates transmembrane signaling and receptor kinase activation. In the present study, isothermal titration calorimetry showed that the Gibbs free energy of VEGF-A, VEGF-C, or VEGF-E binding to D23 or the full-length ECD of VEGFR-2 is dominated by favorable entropic contribution with enthalpic penalty. The free energy of VEGF binding to the ECD is 1.0-1.7 kcal/mol less favorable than for binding to D23. A model of the VEGF-E/VEGFR-2 ECD complex derived from small-angle scattering data provided evidence for homotypic interactions in D4-7. We also solved the crystal structures of complexes between VEGF-A or VEGF-E with D23, which revealed comparable binding surfaces and similar interactions between the ligands and the receptor, but showed variation in D23 twist angles. The energetically unfavorable homotypic interactions in D4-7 may be required for re-orientation of receptor monomers, and this mechanism might prevent ligand-independent activation of VEGFR-2 to evade the deleterious consequences for blood and lymph vessel homeostasis arising from inappropriate receptor activation.

Reviews - 3v6b mentioned but not cited (2)

  1. Structural Basis for Vascular Endothelial Growth Factor Receptor Activation and Implications for Disease Therapy. Shaik F, Cuthbert GA, Homer-Vanniasinkam S, Muench SP, Ponnambalam S, Harrison MA. Biomolecules 10 E1673 (2020)
  2. A Structural Overview of Vascular Endothelial Growth Factors Pharmacological Ligands: From Macromolecules to Designed Peptidomimetics. Ye X, Gaucher JF, Vidal M, Broussy S. Molecules 26 6759 (2021)

Articles - 3v6b mentioned but not cited (3)

  1. Structural and mechanistic insights into VEGF receptor 3 ligand binding and activation. Leppänen VM, Tvorogov D, Kisko K, Prota AE, Jeltsch M, Anisimov A, Markovic-Mueller S, Stuttfeld E, Goldie KN, Ballmer-Hofer K, Alitalo K. Proc Natl Acad Sci U S A 110 12960-12965 (2013)
  2. Biophysical Studies of the Induced Dimerization of Human VEGF Receptor 1 Binding Domain by Divalent Metals Competing with VEGF-A. Gaucher JF, Reille-Seroussi M, Gagey-Eilstein N, Broussy S, Coric P, Seijo B, Lascombe MB, Gautier B, Liu WQ, Huguenot F, Inguimbert N, Bouaziz S, Vidal M, Broutin I. PLoS One 11 e0167755 (2016)
  3. Inhibition of transforming growth factor-beta by Tranilast reduces tumor growth and ameliorates fibrosis in colorectal cancer. Hashemzehi M, Yavari N, Rahmani F, Asgharzadeh F, Soleimani A, Shakour N, Avan A, Hadizadeh F, Fakhraie M, Marjaneh RM, Ferns GA, Reisi P, Ryzhikov M, Khazaei M, Hassanian SM. EXCLI J 20 601-613 (2021)


Reviews citing this publication (13)

  1. Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2. Peach CJ, Mignone VW, Arruda MA, Alcobia DC, Hill SJ, Kilpatrick LE, Woolard J. Int J Mol Sci 19 E1264 (2018)
  2. Molecular Bases of VEGFR-2-Mediated Physiological Function and Pathological Role. Wang X, Bove AM, Simone G, Ma B. Front Cell Dev Biol 8 599281 (2020)
  3. Vascular endothelial growth factor-B in physiology and disease. Bry M, Kivelä R, Leppänen VM, Alitalo K. Physiol Rev 94 779-794 (2014)
  4. Targeting VEGF signalling via the neuropilin co-receptor. Djordjevic S, Driscoll PC. Drug Discov Today 18 447-455 (2013)
  5. Function of members of the neuropilin family as essential pleiotropic cell surface receptors. Parker MW, Guo HF, Li X, Linkugel AD, Vander Kooi CW. Biochemistry 51 9437-9446 (2012)
  6. Extracellular assembly and activation principles of oncogenic class III receptor tyrosine kinases. Verstraete K, Savvides SN. Nat Rev Cancer 12 753-766 (2012)
  7. Targeting extracellular domains D4 and D7 of vascular endothelial growth factor receptor 2 reveals allosteric receptor regulatory sites. Hyde CA, Giese A, Stuttfeld E, Abram Saliba J, Villemagne D, Schleier T, Binz HK, Ballmer-Hofer K. Mol Cell Biol 32 3802-3813 (2012)
  8. Glioma-Targeted Therapeutics: Computer-Aided Drug Design Prospective. Poonan P, Agoni C, Ibrahim MAA, Soliman MES. Protein J 40 601-655 (2021)
  9. Exploitation of receptor tyrosine kinases by viral-encoded growth factors. Lateef Z, Wise LM. Growth Factors 36 118-140 (2018)
  10. Receptors that bind to PEDF and their therapeutic roles in retinal diseases. Xu M, Chen X, Yu Z, Li X. Front Endocrinol (Lausanne) 14 1116136 (2023)
  11. Structural insights into regulation of CCN protein activities and functions. Monsen VT, Attramadal H. J Cell Commun Signal 17 371-390 (2023)
  12. Recent advances of anti-angiogenic inhibitors targeting VEGF/VEGFR axis. Wang L, Liu WQ, Broussy S, Han B, Fang H. Front Pharmacol 14 1307860 (2023)
  13. Structure-Based Design of Peptides Targeting VEGF/VEGFRs. Di Stasi R, De Rosa L, D'Andrea LD. Pharmaceuticals (Basel) 16 851 (2023)

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  1. Inhibition of tumor angiogenesis and growth by a small-molecule multi-FGF receptor blocker with allosteric properties. Bono F, De Smet F, Herbert C, De Bock K, Georgiadou M, Fons P, Tjwa M, Alcouffe C, Ny A, Bianciotto M, Jonckx B, Murakami M, Lanahan AA, Michielsen C, Sibrac D, Dol-Gleizes F, Mazzone M, Zacchigna S, Herault JP, Fischer C, Rigon P, Ruiz de Almodovar C, Claes F, Blanc I, Poesen K, Zhang J, Segura I, Gueguen G, Bordes MF, Lambrechts D, Broussy R, van de Wouwer M, Michaux C, Shimada T, Jean I, Blacher S, Noel A, Motte P, Rom E, Rakic JM, Katsuma S, Schaeffer P, Yayon A, Van Schepdael A, Schwalbe H, Gervasio FL, Carmeliet G, Rozensky J, Dewerchin M, Simons M, Christopoulos A, Herbert JM, Carmeliet P. Cancer Cell 23 477-488 (2013)
  2. VEGFR-2 conformational switch in response to ligand binding. Sarabipour S, Ballmer-Hofer K, Hristova K. Elife 5 e13876 (2016)
  3. Fully quantified spectral imaging reveals in vivo membrane protein interactions. King C, Stoneman M, Raicu V, Hristova K. Integr Biol (Camb) 8 216-229 (2016)
  4. Stable RAGE-heparan sulfate complexes are essential for signal transduction. Xu D, Young JH, Krahn JM, Song D, Corbett KD, Chazin WJ, Pedersen LC, Esko JD. ACS Chem Biol 8 1611-1620 (2013)
  5. 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)
  6. RET recognition of GDNF-GFRα1 ligand by a composite binding site promotes membrane-proximal self-association. Goodman KM, Kjær S, Beuron F, Knowles PP, Nawrotek A, Burns EM, Purkiss AG, George R, Santoro M, Morris EP, McDonald NQ. Cell Rep 8 1894-1904 (2014)
  7. News Structure and function of vascular endothelial growth factor and its receptor system. Park SA, Jeong MS, Ha KT, Jang SB. BMB Rep 51 73-78 (2018)
  8. The basis for the distinct biological activities of vascular endothelial growth factor receptor-1 ligands. Anisimov A, Leppänen VM, Tvorogov D, Zarkada G, Jeltsch M, Holopainen T, Kaijalainen S, Alitalo K. Sci Signal 6 ra52 (2013)
  9. A polymer nanoparticle with engineered affinity for a vascular endothelial growth factor (VEGF165). Koide H, Yoshimatsu K, Hoshino Y, Lee SH, Okajima A, Ariizumi S, Narita Y, Yonamine Y, Weisman AC, Nishimura Y, Oku N, Miura Y, Shea KJ. Nat Chem 9 715-722 (2017)
  10. Involvement of αvβ3 integrin in gremlin-induced angiogenesis. Ravelli C, Mitola S, Corsini M, Presta M. Angiogenesis 16 235-243 (2013)
  11. Real-time analysis of the binding of fluorescent VEGF165a to VEGFR2 in living cells: Effect of receptor tyrosine kinase inhibitors and fate of internalized agonist-receptor complexes. Kilpatrick LE, Friedman-Ohana R, Alcobia DC, Riching K, Peach CJ, Wheal AJ, Briddon SJ, Robers MB, Zimmerman K, Machleidt T, Wood KV, Woolard J, Hill SJ. Biochem Pharmacol 136 62-75 (2017)
  12. Structural and functional characterization of alternative transmembrane domain conformations in VEGF receptor 2 activation. Manni S, Mineev KS, Usmanova D, Lyukmanova EN, Shulepko MA, Kirpichnikov MP, Winter J, Matkovic M, Deupi X, Arseniev AS, Ballmer-Hofer K. Structure 22 1077-1089 (2014)
  13. Contribution of vascular endothelial growth factor receptor-2 sialylation to the process of angiogenesis. Chiodelli P, Rezzola S, Urbinati C, Federici Signori F, Monti E, Ronca R, Presta M, Rusnati M. Oncogene 36 6531-6541 (2017)
  14. Targeting VEGF with LNA-stabilized G-rich oligonucleotide for efficient breast cancer inhibition. Edwards SL, Poongavanam V, Kanwar JR, Roy K, Hillman KM, Prasad N, Leth-Larsen R, Petersen M, Marušič M, Plavec J, Wengel J, Veedu RN. Chem Commun (Camb) 51 9499-9502 (2015)
  15. The impact of the receptor binding profiles of the vascular endothelial growth factors on their angiogenic features. Nieminen T, Toivanen PI, Rintanen N, Heikura T, Jauhiainen S, Airenne KJ, Alitalo K, Marjomäki V, Ylä-Herttuala S. Biochim Biophys Acta 1840 454-463 (2014)
  16. A peptide derived from TIMP-3 inhibits multiple angiogenic growth factor receptors and tumour growth and inflammatory arthritis in mice. Chen YY, Brown NJ, Jones R, Lewis CE, Mujamammi AH, Muthana M, Seed MP, Barker MD. Angiogenesis 17 207-219 (2014)
  17. Modulating Angiogenesis by Proteomimetics of Vascular Endothelial Growth Factor. Abdulkadir S, Li C, Jiang W, Zhao X, Sang P, Wei L, Hu Y, Li Q, Cai J. J Am Chem Soc 144 270-281 (2022)
  18. Simultaneous targeting of two ligand-binding sites on VEGFR2 using biparatopic Affibody molecules results in dramatically improved affinity. Fleetwood F, Klint S, Hanze M, Gunneriusson E, Frejd FY, Ståhl S, Löfblom J. Sci Rep 4 7518 (2014)
  19. Complex Formation between VEGFR2 and the β2-Adrenoceptor. Kilpatrick LE, Alcobia DC, White CW, Peach CJ, Glenn JR, Zimmerman K, Kondrashov A, Pfleger KDG, Ohana RF, Robers MB, Wood KV, Sloan EK, Woolard J, Hill SJ. Cell Chem Biol 26 830-841.e9 (2019)
  20. Dual Action of Sulfated Hyaluronan on Angiogenic Processes in Relation to Vascular Endothelial Growth Factor-A. Koehler L, Ruiz-Gómez G, Balamurugan K, Rother S, Freyse J, Möller S, Schnabelrauch M, Köhling S, Djordjevic S, Scharnweber D, Rademann J, Pisabarro MT, Hintze V. Sci Rep 9 18143 (2019)
  21. Functional and structural characterization of the kinase insert and the carboxy terminal domain in VEGF receptor 2 activation. Manni S, Kisko K, Schleier T, Missimer J, Ballmer-Hofer K. FASEB J 28 4914-4923 (2014)
  22. Unveiling a VEGF-mimetic peptide sequence in the IQGAP1 protein. Capasso D, Di Gaetano S, Celentano V, Diana D, Festa L, Di Stasi R, De Rosa L, Fattorusso R, D'Andrea LD. Mol Biosyst 13 1619-1629 (2017)
  23. Anti-Angiogenic Properties of Ginsenoside Rg3 Epimers: In Vitro Assessment of Single and Combination Treatments. Nakhjavani M, Smith E, Yeo K, Palethorpe HM, Tomita Y, Price TJ, Townsend AR, Hardingham JE. Cancers (Basel) 13 2223 (2021)
  24. Characterization of a drug-targetable allosteric site regulating vascular endothelial growth factor signaling. Thieltges KM, Avramovic D, Piscitelli CL, Markovic-Mueller S, Binz HK, Ballmer-Hofer K. Angiogenesis 21 533-543 (2018)
  25. Development of a highly-potent anti-angiogenic VEGF8-109 heterodimer by directed blocking of its VEGFR-2 binding site. Ghavamipour F, Shahangian SS, Sajedi RH, Arab SS, Mansouri K, Mansouri K, Aghamaali MR. FEBS J 281 4479-4494 (2014)
  26. A Novel Human Long Noncoding RNA SCDAL Promotes Angiogenesis through SNF5-Mediated GDF6 Expression. Wu R, Hu W, Chen H, Wang Y, Li Q, Xiao C, Fan L, Zhong Z, Chen X, Lv K, Zhong S, Shi Y, Chen J, Zhu W, Zhang J, Hu X, Wang J. Adv Sci (Weinh) 8 e2004629 (2021)
  27. Heparin-binding VEGFR1 variants as long-acting VEGF inhibitors for treatment of intraocular neovascular disorders. Xin H, Biswas N, Li P, Zhong C, Chan TC, Nudleman E, Ferrara N. Proc Natl Acad Sci U S A 118 e1921252118 (2021)
  28. A conformation-based phage-display panning to screen neutralizing anti-VEGF VHHs with VEGFR2 mimicry behavior. Shahangian SS, H Sajedi R, Hasannia S, Jalili S, Mohammadi M, Taghdir M, Shali A, Mansouri K, Sariri R. Int J Biol Macromol 77 222-234 (2015)
  29. VEGFR-2 redirected CAR-T cells are functionally impaired by soluble VEGF-A competition for receptor binding. Lanitis E, Kosti P, Ronet C, Cribioli E, Rota G, Spill A, Reichenbach P, Zoete V, Dangaj Laniti D, Coukos G, Irving M. J Immunother Cancer 9 e002151 (2021)
  30. A novel 2-aminobenzimidazole-based compound Jzu 17 exhibits anti-angiogenesis effects by targeting VEGFR-2 signalling. Lien JC, Chung CL, Huang TF, Chang TC, Chen KC, Gao GY, Hsu MJ, Huang SW. Br J Pharmacol 176 4034-4049 (2019)
  31. Elements of the Endomucin Extracellular Domain Essential for VEGF-Induced VEGFR2 Activity. Hu Z, Cano I, Saez-Torres KL, LeBlanc ME, Saint-Geniez M, Ng YS, Argüeso P, D'Amore PA. Cells 9 E1413 (2020)
  32. Multi-physics interactions drive VEGFR2 relocation on endothelial cells. Damioli V, Salvadori A, Beretta GP, Ravelli C, Mitola S. Sci Rep 7 16700 (2017)
  33. Peptide Lv augments L-type voltage-gated calcium channels through vascular endothelial growth factor receptor 2 (VEGFR2) signaling. Shi L, Ko S, Ko ML, Kim AJ, Ko GY. Biochim Biophys Acta 1853 1154-1164 (2015)
  34. Combined Use of Oligopeptides, Fragment Libraries, and Natural Compounds: A Comprehensive Approach To Sample the Druggability of Vascular Endothelial Growth Factor. Bayó-Puxan N, Rodríguez-Mias R, Goldflam M, Kotev M, Ciudad S, Hipolito CJ, Varese M, Suga H, Campos-Olivas R, Barril X, Guallar V, Teixidó M, García J, Giralt E. ChemMedChem 11 928-939 (2016)
  35. Cooperative interactions between VEGFR2 extracellular Ig-like subdomains ensure VEGFR2 dimerization. King C, Wirth D, Workman S, Hristova K. Biochim Biophys Acta Gen Subj 1861 2559-2567 (2017)
  36. Two-faced Fcab prevents polymerization with VEGF and reveals thermodynamics and the 2.15 Å crystal structure of the complex. Lobner E, Humm AS, Mlynek G, Kubinger K, Kitzmüller M, Traxlmayr MW, Djinović-Carugo K, Obinger C. MAbs 9 1088-1104 (2017)
  37. Anti-Angiogenetic and Anti-Lymphangiogenic Effects of a Novel 2-Aminobenzimidazole Derivative, MFB. Hsu MJ, Chen HK, Chen CY, Lien JC, Gao JY, Huang YH, Hsu JB, Lee GA, Huang SW. Front Oncol 12 862326 (2022)
  38. Shifts in renin-angiotensin system components, angiogenesis, and oxidative stress-related protein expression in the lamina cribrosa region of streptozotocin-induced diabetic mice. Qian X, Lin L, Zong Y, Yuan Y, Dong Y, Fu Y, Shao W, Li Y, Gao Q. Graefes Arch Clin Exp Ophthalmol 256 525-534 (2018)
  39. 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)
  40. A dose-escalating toxicology study of the candidate biologic ELP-VEGF. Waller JP, Burke SP, Engel J, Chade AR, Bidwell GL. Sci Rep 11 6216 (2021)
  41. Functional antibody characterization via direct structural analysis and information-driven protein-protein docking. Depetris RS, Lu D, Polonskaya Z, Zhang Z, Luna X, Tankard A, Kolahi P, Drummond M, Williams C, Ebert MCCJC, Patel JP, Poyurovsky MV. Proteins 90 919-935 (2022)
  42. Identification of Potent VEGF Inhibitors for the Clinical Treatment of Glioblastoma, A Virtual Screening Approach. Yadav M, Khandelwal R, Mudgal U, Srinitha S, Khandekar N, Nayarisseri A, Vuree S, Singh SK. Asian Pac J Cancer Prev 20 2681-2692 (2019)
  43. Sulfono-γ-AApeptides as Protein Helical Domain Mimetics to Manipulate the Angiogenesis. Xue S, Wang L, Cai J. Chembiochem 23 e202200298 (2022)
  44. A Cyclic Peptide Epitope of an Under-Explored VEGF-B Loop 1 Demonstrated In Vivo Anti-Angiogenic and Anti-Tumor Activities. Wang L, Xu M, Hu H, Zhang L, Ye F, Jin J, Fang H, Chen J, Chen G, Broussy S, Vidal M, Lv Z, Liu WQ. Front Pharmacol 12 734544 (2021)
  45. Biochemical and Conformational Characterization of Recombinant VEGFR2 Domain 7. Di Stasi R, Diana D, De Rosa L, Fattorusso R, D'Andrea LD. Mol Biotechnol 61 860-872 (2019)
  46. Cholenic acid derivative UniPR1331 impairs tumor angiogenesis via blockade of VEGF/VEGFR2 in addition to Eph/ephrin. Rusnati M, Paiardi G, Tobia C, Urbinati C, Lodola A, D'Ursi P, Corrado M, Castelli R, Wade RC, Tognolini M, Chiodelli P. Cancer Gene Ther 29 908-917 (2022)
  47. Creation of different bioluminescence resonance energy transfer based biosensors with high affinity to VEGF. Stumpf C, Wimmer T, Lorenz B, Stieger K. PLoS One 15 e0230344 (2020)
  48. Engineered ligand-based VEGFR antagonists with increased receptor binding affinity more effectively inhibit angiogenesis. Kapur S, Silverman AP, Ye AZ, Papo N, Jindal D, Blumenkranz MS, Cochran JR. Bioeng Transl Med 2 81-91 (2017)
  49. Estimating binding free energy of a putative growth factors EGF-VEGF complex - a computational bioanalytical study. Lin MH, Chang CA, Fischer WB. J Biomol Struct Dyn 34 1717-1724 (2016)
  50. Human Recombinant VEGFR2D4 Biochemical Characterization to Investigate Novel Anti-VEGFR2D4 Antibodies for Allosteric Targeting of VEGFR2. Di Stasi R, De Rosa L, Diana D, Fattorusso R, D'Andrea LD. Mol Biotechnol 61 513-520 (2019)
  51. Novel hKDR mouse model depicts the antiangiogenesis and apoptosis-promoting effects of neutralizing antibodies targeting vascular endothelial growth factor receptor 2. Cao Y, Sun C, Huo G, Wang H, Wu Y, Wang F, Liu S, Zhai S, Zhang X, Zhao H, Hu M, Gu W, Yang Y, Wang S, Liang C, Lyu J, Lu T, Wang Y, Xie L, Fan C. Cancer Sci 114 115-128 (2023)
  52. 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)
  53. Structure-Based Virtual Screening, Molecular Docking, and Molecular Dynamics Simulation of VEGF inhibitors for the clinical treatment of Ovarian Cancer. Mukherjee S, Abdalla M, Yadav M, Madhavi M, Bhrdwaj A, Khandelwal R, Prajapati L, Panicker A, Chaudhary A, Albrakati A, Hussain T, Nayarisseri A, Singh SK. J Mol Model 28 100 (2022)
  54. NRP1 interacts with endoglin and VEGFR2 to modulate VEGF signaling and endothelial cell sprouting. Sharma S, Ehrlich M, Zhang M, Blobe GC, Henis YI. Commun Biol 7 112 (2024)
  55. Structure-Guided Molecular Engineering of a Vascular Endothelial Growth Factor Antagonist to Treat Retinal Diseases. Kureshi R, Zhu A, Shen J, Tzeng SY, Astrab LR, Sargunas PR, Green JJ, Campochiaro PA, Spangler JB. Cell Mol Bioeng 13 405-418 (2020)
  56. Differential antiangiogenic and anticancer activities of the active metabolites of ginsenoside Rg3. Nakhjavani M, Smith E, Yeo K, Tomita Y, Price TJ, Yool A, Townsend AR, Hardingham JE. J Ginseng Res 48 171-180 (2024)
  57. Elucidating activation and deactivation dynamics of VEGFR-2 transmembrane domain with coarse-grained molecular dynamics simulations. Go YJ, Kalathingal M, Rhee YM. PLoS One 18 e0281781 (2023)


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