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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...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2012
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351436/ https://www.ncbi.nlm.nih.gov/pubmed/22606323 http://dx.doi.org/10.1371/journal.pone.0036990 |
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author | Pagano, Katiuscia Torella, Rubben Foglieni, Chiara Bugatti, Antonella Tomaselli, Simona Zetta, Lucia Presta, Marco Rusnati, Marco Taraboletti, Giulia Colombo, Giorgio Ragona, Laura |
author_facet | Pagano, Katiuscia Torella, Rubben Foglieni, Chiara Bugatti, Antonella Tomaselli, Simona Zetta, Lucia Presta, Marco Rusnati, Marco Taraboletti, Giulia Colombo, Giorgio Ragona, Laura |
author_sort | Pagano, Katiuscia |
collection | PubMed |
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 | Online Article Text |
id | pubmed-3351436 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2012 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-33514362012-05-17 Direct and Allosteric Inhibition of the FGF2/HSPGs/FGFR1 Ternary Complex Formation by an Antiangiogenic, Thrombospondin-1-Mimic Small Molecule Pagano, Katiuscia Torella, Rubben Foglieni, Chiara Bugatti, Antonella Tomaselli, Simona Zetta, Lucia Presta, Marco Rusnati, Marco Taraboletti, Giulia Colombo, Giorgio Ragona, Laura PLoS One Research Article 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. Public Library of Science 2012-05-14 /pmc/articles/PMC3351436/ /pubmed/22606323 http://dx.doi.org/10.1371/journal.pone.0036990 Text en Pagano et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Pagano, Katiuscia Torella, Rubben Foglieni, Chiara Bugatti, Antonella Tomaselli, Simona Zetta, Lucia Presta, Marco Rusnati, Marco Taraboletti, Giulia Colombo, Giorgio Ragona, Laura Direct and Allosteric Inhibition of the FGF2/HSPGs/FGFR1 Ternary Complex Formation by an Antiangiogenic, Thrombospondin-1-Mimic Small Molecule |
title | 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_short | 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 |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3351436/ https://www.ncbi.nlm.nih.gov/pubmed/22606323 http://dx.doi.org/10.1371/journal.pone.0036990 |
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