8ypk

mouse proteasome 20S subunit in complex with compound 1

spinqualitylabelsall models 8ypk, resolution 2.70Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8ypk is a 20 chain structure with sequence from Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 2.7Å Ligands: A1L0C Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PSA4_MOUSE 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. Publication Abstract from PubMed The immunoproteasome subunit LMP7 (beta5i)/LMP2 (beta1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit beta5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over beta5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of alpha-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor 19. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with 19 explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that 19 is orally bioavailable and shows promise as potential treatment for autoimmune diseases. Optimization of alpha-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 (beta5i)/LMP2 (beta1i) dual inhibitor.,Arai Y, Shitama H, Yamagishi M, Ono S, Kashima A, Hiraizumi M, Tsuda N, Katayama K, Tanaka K, Koda Y, Kato S, Sakata K, Nureki O, Miyazaki H Bioorg Med Chem. 2024 Jul 15;109:117790. doi: 10.1016/j.bmc.2024.117790. Epub , 2024 Jun 12. PMID:38906067 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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