In silico investigation of extracellular domain of RAGE receptor interaction with A-box and B-box of HMGB1 protein

Abstract

HMGB1 protein which is a non-histone chromosomal protein with two functional domains named A-box and B-box can also act as a signaling molecule after releasing from the cell and binding to the cell surface receptors such as RAGE. HMGB1 through its B-box domain binds to extracellular domain of RAGE and activates the signaling pathways involved in various pathological conditions like sepsis and tumor growth and metastasis. Interaction of recombinant HMGB1 A-box with RAGEantagonizes the RAGE activation by HMGB1. In the present study, interaction of human RAGE (hRAGE) extracellular domain (VC1C2) and B-box and A-box of human HMGB1 (hHMGB1) was investigated using a protein-protein docking software, HADDOCK. The results obtained were analyzed by PyMOL and LigPlot softwares. The results show B-box and A-box bind to different sites on the VC1domain of RAGE and one of the B-box binding points is a positively charged groove located on the V domain surface which is also a major binding site for another RAGE ligand, Advanced Glycation Endproducts (AGEs). The obtained results can be utilized to design new potent drugs for treatment of HMGB1-RAGE-related diseases such as cancer and sepsis.

Keywords

• human HMGB1
• human RAGE
• HADDOCK software
• cancer
• sepsis