Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule

Katiuscia Pagano, Rubben Torella, Chiara Foglieni, Antonella Bugatti, Simona Tomaselli, Lucia Zetta, Marco Presta, Marco Rusnati, Giulia Taraboletti, Giorgio Colombo, Laura Ragona

Research output: Contribution to journalArticle

22 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere36990
JournalPLoS One
Volume7
Issue number5
DOIs
Publication statusPublished - May 14 2012

Fingerprint

Thrombospondin 1
Heparan Sulfate Proteoglycans
proteoglycans
Fibroblast Growth Factor 2
angiogenesis
receptors
Molecules
surface plasmon resonance
fibroblast growth factors
molecular dynamics
heparin
assays
Assays
tyrosine
Nuclear magnetic resonance
nuclear magnetic resonance spectroscopy
binding sites
phosphotransferases (kinases)
Angiogenesis Inhibitors
cells

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

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.

In: PLoS One, Vol. 7, No. 5, e36990, 14.05.2012.

Research output: Contribution to journalArticle

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. In: PLoS One. 2012 ; Vol. 7, No. 5.
@article{0fac814e23cd414da0aec284dbab1875,
title = "Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule",
abstract = "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.",
author = "Katiuscia Pagano and Rubben Torella and Chiara Foglieni and Antonella Bugatti and Simona Tomaselli and Lucia Zetta and Marco Presta and Marco Rusnati and Giulia Taraboletti and Giorgio Colombo and Laura Ragona",
year = "2012",
month = "5",
day = "14",
doi = "10.1371/journal.pone.0036990",
language = "English",
volume = "7",
journal = "PLoS One",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "5",

}

TY - JOUR

T1 - Direct and allosteric inhibition of the FGF2/HSPGs/FGFR1 ternary complex formation by an antiangiogenic, thrombospondin-1-mimic small molecule

AU - Pagano, Katiuscia

AU - Torella, Rubben

AU - Foglieni, Chiara

AU - Bugatti, Antonella

AU - Tomaselli, Simona

AU - Zetta, Lucia

AU - Presta, Marco

AU - Rusnati, Marco

AU - Taraboletti, Giulia

AU - Colombo, Giorgio

AU - Ragona, Laura

PY - 2012/5/14

Y1 - 2012/5/14

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84860993410&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84860993410&partnerID=8YFLogxK

U2 - 10.1371/journal.pone.0036990

DO - 10.1371/journal.pone.0036990

M3 - Article

C2 - 22606323

AN - SCOPUS:84860993410

VL - 7

JO - PLoS One

JF - PLoS One

SN - 1932-6203

IS - 5

M1 - e36990

ER -