Search results for "immunoproteasome"
showing 3 items of 3 documents
Exploring the non-covalent ligand-binding mechanism on immunoproteasome by enhanced Molecular Dynamics
2021
Selective inhibition of immunoproteasome is a valuable strategy to treat autoimmune and inflammatory diseases, and hematologic malignancies. In particular, non-covalent inhibition is strongly desirable because it is free of the drawbacks and side effects associated with covalent inhibition. Recently, a new series of amide derivatives with Ki values in the low/submicromolar ranges toward the β1i subunit have been identified as non-covalent inhibitors 1 . We investigated the binding mechanism of the most potent and selective inhibitor (1) to elucidate the steps from the ligand entrance into the binding pocket to the ligand-induced conformational changes. We carried out a total of 400ns of MD-…
Immunoproteasome LMP2 60HH Variant Alters MBP Epitope Generation and Reduces the Risk to Develop Multiple Sclerosis in Italian Female Population
2010
BackgroundAlbeit several studies pointed out the pivotal role that CD4+T cells have in Multiple Sclerosis, the CD8+ T cells involvement in the pathology is still in its early phases of investigation. Proteasome degradation is the key step in the production of MHC class I-restricted epitopes and therefore its activity could be an important element in the activation and regulation of autoreactive CD8+ T cells in Multiple Sclerosis.Methodology/principal findingsImmunoproteasomes and PA28-alphabeta regulator are present in MS affected brain area and accumulated in plaques. They are expressed in cell types supposed to be involved in MS development such as neurons, endothelial cells, oligodendroc…
Immunoproteasome and Non-Covalent Inhibition: Exploration by Advanced Molecular Dynamics and Docking Methods
2021
The selective inhibition of immunoproteasome is a valuable strategy to treat autoimmune, inflammatory diseases, and hematologic malignancies. Recently, a new series of amide derivatives as non-covalent inhibitors of the β1i subunit with Ki values in the low/submicromolar ranges have been identified. Here, we investigated the binding mechanism of the most potent and selective inhibitor, N-benzyl-2-(2-oxopyridin-1(2H)-yl)propanamide (1), to elucidate the steps from the ligand entrance into the binding pocket to the ligand-induced conformational changes. We carried out a total of 400 ns of MD-binding analyses, followed by 200 ns of plain MD. The trajectories clustering allowed identifying thre…