Molecular mechanism of inhibition of nonclassical FGF-1 export
by Rajalingam, D.; Kumar, T. K. S.; Soldi, R.; Graziani, I.; Prudovsky, I.; Yu, C.
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 Cu2+-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.
- Journal
- Biochemistry
- Volume
- 44
- Issue
- 47
- Year
- 2005
- Start Page
- 15472-15479
- URL
- https://dx.doi.org/10.1021/bi0516071
- ISBN/ISSN
- 1520-4995; 0006-2960
- DOI
- 10.1021/bi0516071