title: Molecular mechanism of inhibition of nonclassical FGF-1 export.
abstract: Fibroblast growth factor (FGF-1) lacks a signal sequence and is exported by an unconventional release mechanism. The nonclassical export of FGF-1 has been shown to be inhibited by an anti-allergic and anti-inflammatory drug, amlexanox (AMX). We investigate the molecular mechanism(s) underlying the inhibitory action of AMX on the release of FGF-1, using a variety of biophysical techniques including multidimensional NMR spectroscopy. AMX binds to FGF-1 and enhances its conformational stability. AMX binds to locations close to Cys30 and sterically blocks Cu(2+)-induced oxidation, leading to the formation of the homodimer of FGF-1. AMX-induced inhibition of the formation of the FGF-1 homodimer is observed both under cell-free conditions and in living cells. Results of this study suggest a novel approach for the design of drugs against FGF-1-mediated disorders.
authors.affiliation: Department of Chemistry and Biochemistry, University of Arkansas, Fayetteville, Arkansas 72701, USA.
authors.forename: Dakshinamurthy
authors.initials: D
authors.lastname: Rajalingam
authors.forename: Thallapuranam Krishnaswamy S
authors.initials: TK
authors.lastname: Kumar
authors.forename: Raffaella
authors.initials: R
authors.lastname: Soldi
authors.forename: Irene
authors.initials: I
authors.lastname: Graziani
authors.forename: Igor
authors.initials: I
authors.lastname: Prudovsky
authors.forename: Chin
authors.initials: C
authors.lastname: Yu
mesh_terms: D000631:Aminopyridines / Q000737:chemistry / Q000494:pharmacology; D018926:Anti-Allergic Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D003198:Computer Simulation; D003300:Copper / Q000494:pharmacology; D016220:Fibroblast Growth Factor 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D006358:Hot Temperature; D006801:Humans; D019906:Nuclear Magnetic Resonance, Biomolecular; D010084:Oxidation-Reduction; D011485:Protein Binding; D011489:Protein Denaturation / Q000187:drug effects; D021381:Protein Transport
chemical_list: D000631:Aminopyridines; D018926:Anti-Allergic Agents; D016220:Fibroblast Growth Factor 1; D003300:Copper; C045742:amlexanox