In silico investigation of extracellular domain of RAGE receptor interaction with A-box and B-box of HMGB1 protein | In silico raziskava zunajcelične domene receptorja RAGE v interakciji z A-box in B-box proteina HMGB1

English. 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.  

Slovenian. Protein HMGB1 je nehistonski kromosomski protein z dvema funkcionalnima domenama, A-box in B-box, ki lahko po sprostitvi iz celice deluje tudi kot signalna molekula in se veže na celično površino preko receptorjev kot je RAGE. HMBG1 se preko domene B-box veže na zunajcelično domeno RAGE in aktivira signalne poti, ki so vključene v različna patološka stanja kot so sepsa, rast tumorja in metastaze. Interakcija rekombinantnega proteina HMGB1 A-box z RAGE deluje antagonistično. V raziskavi smo preučevali interakcijo ekstracelularne domene (VC1C2) humanega RAGE (hRAGE) z B-box ter A-box humanega HMHB1 (hHMGB1). Uporabili smo računalniško orodje HADDOCK, pridobljene rezultate smo analizirali s programoma PyMOL in LigPlot. Rezultati so pokazali, da B-box in A-box vežeta na različna mesta domene VC1 na RAGE. Eno od vezavnih mest B-box je pozitivno nabita vdolbina na površini domene V in je hkrati glavno vezavno mesto za druge RAGE-ligande (Advanced Glycation End products – AGE). Rezultati raziskave so uporabni za načrtovanje novih zdravil za zdravljenje bolezni povezanih z interakcijami HMGB1-RAGE, kot sta rak in sepsa.