Open AccessDirect and Allosteric Inhibition of the FGF2/HSPGs/FGFR1 Ternary Complex Formation by an Antiangiogenic, Thrombospondin-1-Mimic Small Molecule
Author(s) -
Katiuscia Pagano,
Rubben Torella,
Chiara Foglieni,
Antonella Bugatti,
Simona Tomaselli,
Lucia Zetta,
Marco Presta,
Marco Rusnati,
Giulia Taraboletti,
Giorgio Colombo,
Laura Ragona
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0036990
Subject(s) - allosteric regulation , angiogenesis , fibroblast growth factor , receptor tyrosine kinase , microbiology and biotechnology , surface plasmon resonance , ternary complex , receptor , fibroblast growth factor receptor 1 , fibroblast growth factor receptor , small molecule , biochemistry , tyrosine kinase inhibitor , chemistry , tyrosine kinase , biology , g protein coupled receptor , biophysics , cancer research , cancer , genetics , enzyme , materials science , nanotechnology , nanoparticle
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.