title: Tranilast Blocks the Interaction between the Protein S100A11 and Receptor for Advanced Glycation End Products (RAGE) V Domain and Inhibits Cell Proliferation.
abstract: The human S100 calcium-binding protein A11 (S100A11) is a member of the S100 protein family. Once S100A11 proteins bind to calcium ions at EF-hand motifs, S100A11 changes its conformation, promoting interaction with target proteins. The receptor for advanced glycation end products (RAGE) consists of three extracellular domains, including the V domain, C1 domain, and C2 domain. In this case, the V domain is the target for mutant S100A11 (mS100A11) binding. RAGE binds to the ligands, resulting in cell proliferation, cell growth, and several signal transduction cascades. We used NMR and fluorescence spectroscopy to demonstrate the interactions between mS100A11and RAGE V domain. The tranilast molecule is a drug used for treating allergic disorders. We discovered that the RAGE V domain and tranilast would interact with mS100A11 by using (1)H-(15)N HSQC NMR titrations. According to the results, we obtained two binary complex models from the HADDOCK program, S100A11-RAGE V domain and S100A11-tranilast, respectively. We overlapped two binary complex models with the same orientation of S100A11 homodimer and demonstrated that tranilast would block the binding site between S100A11 and the RAGE V domain. We further utilized a water-soluble tetrazolium-1 assay to confirm this result. We think that the results will be potentially useful in the development of new anti-cancer drugs.
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
authors.forename: Yen-Kai
authors.initials: YK
authors.lastname: Huang
authors.affiliation: Graduate Institute of Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung 40454, Taiwan.
authors.forename: Ruey-Hwang
authors.initials: RH
authors.lastname: Chou
authors.affiliation: Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan. Electronic address: cyu.nthu@gmail.com.
authors.forename: Chin
authors.initials: C
authors.lastname: Yu
mesh_terms: D049109:Cell Proliferation / Q000187:drug effects*; D005453:Fluorescence; D006801:Humans; D008958:Models, Molecular; D019906:Nuclear Magnetic Resonance, Biomolecular; D011485:Protein Binding; D000067759:Receptor for Advanced Glycation End Products / Q000378:metabolism*; D009418:S100 Proteins / Q000737:chemistry / Q000378:metabolism*; D014364:Tryptophan / Q000378:metabolism; D062367:ortho-Aminobenzoates / Q000494:pharmacology*
chemical_list: C000593871:AGER protein, human; D000067759:Receptor for Advanced Glycation End Products; D009418:S100 Proteins; D062367:ortho-Aminobenzoates; C072337:S100A11 protein, human; D014364:Tryptophan; C012293:tranilast
keywords: S100 proteins; cell proliferation; nuclear magnetic resonance (NMR); protein complex; protein purification; receptor for advanced glycation end products (RAGE); tranilast