6e5b | pdb_00006e5b

Human Immunoproteasome 20S particle in complex with compound 1

spinqualitylabelsall models 6e5b, resolution 2.77Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 6e5b is a 20 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.77Å Ligands: HUJ, NA, SCN Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PSA2_HUMAN The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. PSMA2 may have a potential regulatory effect on another component(s) of the proteasome complex through tyrosine phosphorylation. Publication Abstract from PubMed The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in off-label trials of Systemic Lupus Erythematosus. One potential mechanism of this clinical benefit is from the depletion of pathogenic immune cells (plasmablasts and plasmacytoid dendritic cells). However, bortezomib is cytotoxic against nonimmune cells, which limits its use for autoimmune diseases. An attractive alternative is to selectively inhibit the immune cell-specific immunoproteasome to deplete pathogenic immune cells and spare nonhematopoietic cells. Here, we disclose the development of highly subunit-selective immunoproteasome inhibitors using insights obtained from the first bona fide human immunoproteasome cocrystal structures. Evaluation of these inhibitors revealed that immunoproteasome-specific inhibition does not lead to immune cell death as anticipated and that targeting viability requires inhibition of both immuno- and constitutive proteasomes. CRISPR/Cas9-mediated knockout experiments confirmed upregulation of the constitutive proteasome upon disruption of the immunoproteasome, protecting cells from death. Thus, immunoproteasome inhibition alone is not a suitable approach to deplete immune cells. Design and Evaluation of Highly Selective Human Immunoproteasome Inhibitors Reveal a Compensatory Process That Preserves Immune Cell Viability.,Ladi E, Everett C, Stivala CE, Daniels BE, Durk MR, Harris SF, Huestis MP, Purkey HE, Staben ST, Augustin M, Blaesse M, Steinbacher S, Eidenschenk C, Pappu R, Siu M J Med Chem. 2019 Aug 8;62(15):7032-7041. doi: 10.1021/acs.jmedchem.9b00509. Epub , 2019 Jul 29. PMID:31283222 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proteasome 3D structures

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