8YVP の概要
| エントリーDOI | 10.2210/pdb8yvp/pdb |
| EMDBエントリー | 39612 |
| 分子名称 | Proteasome subunit beta type-7, Proteasome subunit alpha type-5, Proteasome subunit beta type-2, ... (16 entities in total) |
| 機能のキーワード | inhibitor, complex, proteasome, hydrolase |
| 由来する生物種 | Mus musculus (house mouse) 詳細 |
| タンパク質・核酸の鎖数 | 28 |
| 化学式量合計 | 735360.49 |
| 構造登録者 | |
| 主引用文献 | 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 主引用文献が同じPDBエントリー |
| 実験手法 | ELECTRON MICROSCOPY (2.5 Å) |
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