Blocking the Interactions between Calcium-Bound S100A12 Protein and the V Domain of RAGE Using Tranilast
- PLoS One. 2016 Sep 6;11(9):e0162000. doi: 10.1371/journal.pone.0162000.
- 1. Department of Chemistry, National Tsing Hua University, Hsinchu, 30013, Taiwan.
- 2. Northwood High School, Irvine, California, 92620, United States of America.
- 3. Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, 40402, Taiwan.
- 4. Department of Biotechnology, Asia University, Taichung, 41354, Taiwan.
The receptor for advanced glycation end products (RAGE), a transmembrane receptor in the immunoglobulin superfamily, is involved in several inflammatory processes. RAGE induces cellular signaling pathways upon binding with various ligands, such as advanced glycation end products (AGEs), β-amyloids, and S100 proteins. The solution structure of S100A12 and the V ligand-binding region of RAGE have been reported previously. Using heteronuclear NMR spectroscopy to conduct 1H-15N heteronuclear single quantum coherence (HSQC) titration experiments, we identified and mapped the binding interface between S100A12 and the V domain of RAGE. The NMR chemical shift data were used as the constraints for the High Ambiguity Driven biomolecular DOCKing (HADDOCK) calculation to generate a structural model of the S100A12-V domain complex. In addition, tranilast (an anti-allergic drug) showed strong interaction with S100A12 in the 1H-15N HSQC titration, fluorescence experiments, and WST-1 assay. The results also indicated that tranilast was located at the binding site between S100A12 and the V domain, blocking interaction between these two proteins. Our results provide the mechanistic details for a structural model and reveal a potential precursor for an inhibitor for pro-inflammatory diseases, which could be useful for the development of new drugs.