Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule.
Fibroblast growth factors (FGFs) are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation of a ternary complex with the transmembrane tyrosine kinase receptors (FGFRs), and heparan sulphate proteoglycans (HSPGs) is required for FGF...
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2012
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oai:doaj.org-article:061b20b1ac724c3e97bcd6d72331e2bd2021-11-18T07:18:55ZDirect and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule.1932-620310.1371/journal.pone.0036990https://doaj.org/article/061b20b1ac724c3e97bcd6d72331e2bd2012-01-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22606323/?tool=EBIhttps://doaj.org/toc/1932-6203Fibroblast growth factors (FGFs) are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation of a ternary complex with the transmembrane tyrosine kinase receptors (FGFRs), and heparan sulphate proteoglycans (HSPGs) is required for FGF2 pro-angiogenic activity. Here by using a combination of techniques including Nuclear Magnetic Resonance, Molecular Dynamics, Surface Plasmon Resonance and cell-based binding assays we clarify the molecular mechanism of inhibition of an angiostatic small molecule, sm27, mimicking the endogenous inhibitor of angiogenesis, thrombospondin-1. NMR and MD data demonstrate that sm27 engages the heparin-binding site of FGF2 and induces long-range dynamics perturbations along FGF2/FGFR1 interface regions. The functional consequence of the inhibitor binding is an impaired FGF2 interaction with both its receptors, as demonstrated by SPR and cell-based binding assays. We propose that sm27 antiangiogenic activity is based on a twofold-direct and allosteric-mechanism, inhibiting FGF2 binding to both its receptors.Katiuscia PaganoRubben TorellaChiara FoglieniAntonella BugattiSimona TomaselliLucia ZettaMarco PrestaMarco RusnatiGiulia TarabolettiGiorgio ColomboLaura RagonaPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 7, Iss 5, p e36990 (2012) |
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Medicine R Science Q Katiuscia Pagano Rubben Torella Chiara Foglieni Antonella Bugatti Simona Tomaselli Lucia Zetta Marco Presta Marco Rusnati Giulia Taraboletti Giorgio Colombo Laura Ragona Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule. |
| description |
Fibroblast growth factors (FGFs) are recognized targets for the development of therapies against angiogenesis-driven diseases, including cancer. The formation of a ternary complex with the transmembrane tyrosine kinase receptors (FGFRs), and heparan sulphate proteoglycans (HSPGs) is required for FGF2 pro-angiogenic activity. Here by using a combination of techniques including Nuclear Magnetic Resonance, Molecular Dynamics, Surface Plasmon Resonance and cell-based binding assays we clarify the molecular mechanism of inhibition of an angiostatic small molecule, sm27, mimicking the endogenous inhibitor of angiogenesis, thrombospondin-1. NMR and MD data demonstrate that sm27 engages the heparin-binding site of FGF2 and induces long-range dynamics perturbations along FGF2/FGFR1 interface regions. The functional consequence of the inhibitor binding is an impaired FGF2 interaction with both its receptors, as demonstrated by SPR and cell-based binding assays. We propose that sm27 antiangiogenic activity is based on a twofold-direct and allosteric-mechanism, inhibiting FGF2 binding to both its receptors. |
| format |
article |
| author |
Katiuscia Pagano Rubben Torella Chiara Foglieni Antonella Bugatti Simona Tomaselli Lucia Zetta Marco Presta Marco Rusnati Giulia Taraboletti Giorgio Colombo Laura Ragona |
| author_facet |
Katiuscia Pagano Rubben Torella Chiara Foglieni Antonella Bugatti Simona Tomaselli Lucia Zetta Marco Presta Marco Rusnati Giulia Taraboletti Giorgio Colombo Laura Ragona |
| author_sort |
Katiuscia Pagano |
| title |
Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule. |
| title_short |
Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule. |
| title_full |
Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule. |
| title_fullStr |
Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule. |
| title_full_unstemmed |
Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule. |
| title_sort |
direct and allosteric inhibition of the fgf2/hspgs/fgfr1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule. |
| publisher |
Public Library of Science (PLoS) |
| publishDate |
2012 |
| url |
https://doaj.org/article/061b20b1ac724c3e97bcd6d72331e2bd |
| work_keys_str_mv |
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1718423577373442048 |