Blocking the Interactions between Calcium-Bound S100A12 Protein and the V Domain of RAGE Using Tranilast

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• The receptor for advanced glycation end products (RAGE) is a key mediator in inflammatory processes, binding various ligands like S100 proteins.
• Understanding the structural basis of RAGE-ligand interactions is crucial for developing targeted therapies for inflammatory diseases.

Purpose of the Study:

• To elucidate the structural mechanism of S100A12 binding to the V domain of RAGE.
• To investigate the potential of tranilast as an inhibitor of the S100A12-RAGE interaction.

Main Methods:

• Heteronuclear NMR spectroscopy (1H-15N HSQC) was employed to map the binding interface between S100A12 and RAGE V domain.
• High Ambiguity Driven biomolecular DOCKing (HADDOCK) was used to generate a structural model of the complex.
• Fluorescence experiments and WST-1 assays were conducted to assess tranilast's interaction with S100A12.

Main Results:

• The binding interface between S100A12 and the RAGE V domain was successfully identified and mapped.
• Tranilast demonstrated a strong interaction with S100A12, localizing to the S100A12-RAGE binding site.
• Tranilast effectively blocked the interaction between S100A12 and the RAGE V domain.

Conclusions:

• A structural model of the S100A12-RAGE V domain complex provides mechanistic insights into their interaction.
• Tranilast acts as an inhibitor by preventing S100A12 binding to RAGE, suggesting its potential as a therapeutic lead.
• These findings pave the way for developing novel inhibitors for pro-inflammatory diseases targeting the RAGE pathway.