N-glycosylation of High Mobility Group Box 1 protein (HMGB1) modulates the interaction with glycyrrhizin: A molecular modeling study |
| |
| Institution: | 1. University of Lille, Inserm, U995 - LIRIC - Lille Inflammation Research International Center, ICPAL, 3 rue du Professeur Laguesse, BP-83, F-59006, Lille, France;2. OncoWitan, Lille (Wasquehal), 59290, France;1. Wroclaw University of Science and Technology, Faculty of Computer Science and Management, 50-371 Wrocław, I. Łukasiewicza Street 5, Poland;2. Jagiellonian University Medical College, Department of Technology and Biotechnology of Drugs, 30-688 Kraków, 9 Medyczna Street, Poland;3. Maj Institute of Pharmacology, Polish Academy of Sciences, Department of Medicinal Chemistry, 31-343 Kraków, Smętna Street 12, Poland;1. OncoWitan, Lille (Wasquehal), 59290, France;2. University of Lille, Inserm, INFINITE - U1286, Institut de Chimie Pharmaceutique Albert Lespagnol (ICPAL), Faculté de Pharmacie, 3 rue du Professeur Laguesse, BP-83, F-59006, Lille, France;1. School of Computer Science and Technology, Harbin Institute of Technology (Shenzhen), Shenzhen, Guangdong 518055, China;2. School of Computer Science and Technology, Harbin Institute of Technology, Harbin, Heilongjiang 150001, China;3. CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China;1. Department of Anesthesiology, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061001, PR China;2. Department of General Surgery, Cangzhou Central Hospital, Cangzhou City, Hebei Province 061001, PR China |
| |
| Abstract: | High Mobility Group Box 1 protein (HMGB1) is an abundant protein with multiple functions in cells, acting as a DNA chaperone and damage-associated molecular pattern molecule. It represents an attractive target for the treatment of inflammatory diseases and cancers. The plant natural product glycyrrhizin (GLR) is a well-characterized ligand of HMGB1 and a drug used to treat diverse liver and skin diseases. The drug is known to bind to each of the two adjacent HMG boxes of the non-glycosylated protein. In cells, HMGB1 is N-glycosylated at three asparagine residues located in boxes A and B, and these N-glycans are essential for the nucleocytoplasmic transport of the protein. But the impact of the N-glycans on drug binding is unknown. Here we have investigated the effect of the N-glycosylation of HMGB1 on its interaction with GLR using molecular modelling, after incorporation of three N-glycans on a Human HMGB1 structure (PDB code 2YRQ). Sialylated bi-antennary N-glycans were introduced on the protein and exposed in a folded or an extended conformation for the drug binding study. The docking of the drug was performed using both 18α- and 18β-epimers of GLR and the conformations and potential energy of interaction (ΔE) of the different drug-protein complexes were compared. The N-glycans do not shield the drug binding sites on boxes A and B but can modulate the drug-protein interaction, via both direct and indirect effects. The calculations indicate that binding of 18α/β-GLR to the HMG box is generally reduced when the protein is N-glycosylated vs. the non-glycosylated protein. In particular, the N-glycans in an extended configuration significantly weaken the binding of GLR to box-B. The effects of the N-glycans are mostly indirect, but in one case a direct contact with the drug, via a carbohydrate-carbohydrate interaction, was observed with 18β-GLR bound to Box-B of glycosylated HMGB1. For the first time, it is shown (at least in silico) that N-glycosylation, one of the many post-translational modifications of HMGB1, can affect drug binding. |
| |
| Keywords: | Glycyrrhizin HMGB1 Protein glycosylation Drug-protein binding Molecular modelling |
| 本文献已被 ScienceDirect 等数据库收录！ |
|
