8YPK
mouse proteasome 20S subunit in complex with compound 1
This is a non-PDB format compatible entry.
Summary for 8YPK
| Entry DOI | 10.2210/pdb8ypk/pdb |
| EMDB information | 39482 |
| Descriptor | Proteasome subunit beta type-6, Proteasome subunit alpha type-5, Proteasome subunit alpha type-4, ... (15 entities in total) |
| Functional Keywords | inhibitor, complex, proteasome, hydrolase |
| Biological source | Mus musculus (house mouse) More |
| Total number of polymer chains | 28 |
| Total formula weight | 734349.66 |
| Authors | Kashima, A.,Arai, Y. (deposition date: 2024-03-17, release date: 2024-07-31, Last modification date: 2024-10-23) |
| Primary citation | 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. Optimization of alpha-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 ( beta 5i)/LMP2 ( beta 1i) dual inhibitor. Bioorg.Med.Chem., 109:117790-117790, 2024 Cited by PubMed Abstract: The immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) 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 β5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over β5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of α-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. PubMed: 38906067DOI: 10.1016/j.bmc.2024.117790 PDB entries with the same primary citation |
| Experimental method | ELECTRON MICROSCOPY (2.7 Å) |
Structure validation
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