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データを開く
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基本情報
| 登録情報 | データベース: PDB / ID: 8yvp | |||||||||
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| タイトル | canine immunoproteasome 20S subunit in complex with compound 1 | |||||||||
要素 |
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キーワード | HYDROLASE / inhibitor / complex / proteasome | |||||||||
| 機能・相同性 | 機能・相同性情報Antigen processing: Ub, ATP-independent proteasomal degradation / Regulation of ornithine decarboxylase (ODC) / Proteasome assembly / Cross-presentation of soluble exogenous antigens (endosomes) / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Degradation of CRY and PER proteins / Cdc20:Phospho-APC/C mediated degradation of Cyclin A ...Antigen processing: Ub, ATP-independent proteasomal degradation / Regulation of ornithine decarboxylase (ODC) / Proteasome assembly / Cross-presentation of soluble exogenous antigens (endosomes) / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / Degradation of CRY and PER proteins / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Assembly of the pre-replicative complex / CDK-mediated phosphorylation and removal of Cdc6 / Autodegradation of the E3 ubiquitin ligase COP1 / G2/M Checkpoints / Degradation of AXIN / Asymmetric localization of PCP proteins / APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1 / SCF(Skp2)-mediated degradation of p27/p21 / Regulation of RUNX3 expression and activity / Regulation of RAS by GAPs / Regulation of PTEN stability and activity / UCH proteinases / Degradation of DVL / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / TNFR2 non-canonical NF-kB pathway / Hedgehog ligand biogenesis / Regulation of RUNX2 expression and activity / Degradation of GLI1 by the proteasome / FBXL7 down-regulates AURKA during mitotic entry and in early mitosis / Hedgehog 'on' state / Orc1 removal from chromatin / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Dectin-1 mediated noncanonical NF-kB signaling / NIK-->noncanonical NF-kB signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / Degradation of beta-catenin by the destruction complex / Activation of NF-kappaB in B cells / The role of GTSE1 in G2/M progression after G2 checkpoint / Degradation of CDH1 / FCERI mediated NF-kB activation / RUNX1 regulates transcription of genes involved in differentiation of HSCs / CLEC7A (Dectin-1) signaling / Interleukin-1 signaling / Separation of Sister Chromatids / Downstream TCR signaling / MAPK6/MAPK4 signaling / ABC-family protein mediated transport / GLI3 is processed to GLI3R by the proteasome / Neddylation / Ub-specific processing proteases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / ER-Phagosome pathway / proteasome core complex / myofibril / immune system process / proteasome endopeptidase complex / NF-kappaB binding / proteasome core complex, beta-subunit complex / threonine-type endopeptidase activity / proteasome core complex, alpha-subunit complex / skeletal muscle tissue development / Neutrophil degranulation / : / proteasome complex / sarcomere / protein catabolic process / P-body / negative regulation of inflammatory response to antigenic stimulus / lipopolysaccharide binding / response to virus / nuclear matrix / peptidase activity / regulation of inflammatory response / response to oxidative stress / endopeptidase activity / proteasome-mediated ubiquitin-dependent protein catabolic process / positive regulation of canonical NF-kappaB signal transduction / cilium / nuclear body / ciliary basal body / ribosome / ubiquitin protein ligase binding / centrosome / mitochondrion / proteolysis / RNA binding / nucleoplasm / identical protein binding / nucleus / cytoplasm / cytosol 類似検索 - 分子機能 | |||||||||
| 生物種 | ![]() | |||||||||
| 手法 | 電子顕微鏡法 / 単粒子再構成法 / 解像度: 2.5 Å | |||||||||
データ登録者 | Kashima, A. / Arai, Y. | |||||||||
| 資金援助 | 1件
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引用 | ジャーナル: Bioorg Med Chem / 年: 2024タイトル: Optimization of α-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual inhibitor. 著者: Yuuki Arai / Hiroaki Shitama / Masahito Yamagishi / Satoshi Ono / Akiko Kashima / Masahiro Hiraizumi / Naoki Tsuda / Koushirou Katayama / Kouji Tanaka / Yuzo Koda / Sayuka Kato / Kei Sakata / ...著者: Yuuki Arai / Hiroaki Shitama / Masahito Yamagishi / Satoshi Ono / Akiko Kashima / Masahiro Hiraizumi / Naoki Tsuda / Koushirou Katayama / Kouji Tanaka / Yuzo Koda / Sayuka Kato / Kei Sakata / Osamu Nureki / Hiroshi Miyazaki / ![]() 要旨: 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 ...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. | |||||||||
| 履歴 |
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構造の表示
| 構造ビューア | 分子: Molmil Jmol/JSmol |
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ダウンロードとリンク
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ダウンロード
| PDBx/mmCIF形式 | 8yvp.cif.gz | 1.2 MB | 表示 | PDBx/mmCIF形式 |
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| PDB形式 | pdb8yvp.ent.gz | 表示 | PDB形式 | |
| PDBx/mmJSON形式 | 8yvp.json.gz | ツリー表示 | PDBx/mmJSON形式 | |
| その他 | その他のダウンロード |
-検証レポート
| アーカイブディレクトリ | https://data.pdbj.org/pub/pdb/validation_reports/yv/8yvp ftp://data.pdbj.org/pub/pdb/validation_reports/yv/8yvp | HTTPS FTP |
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-関連構造データ
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リンク
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集合体
| 登録構造単位 | ![]()
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| 1 |
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要素
-Proteasome subunit beta type- ... , 7種, 14分子 BECDFASXYUaWVT
| #1: タンパク質 | 分子量: 25280.010 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #2: タンパク質 | 分子量: 22554.545 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #6: タンパク質 | 分子量: 22014.920 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #7: タンパク質 | 分子量: 26405.182 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #8: タンパク質 | 分子量: 22988.895 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #9: タンパク質 | 分子量: 29143.053 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #11: タンパク質 | 分子量: 22935.377 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() |
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-Proteasome subunit alpha type- ... , 7種, 14分子 PbQJRKHMINLGOZ
| #3: タンパク質 | 分子量: 25955.549 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #4: タンパク質 | 分子量: 28442.248 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #5: タンパク質 | 分子量: 27405.434 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #10: タンパク質 | 分子量: 26435.977 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #12: タンパク質 | 分子量: 27897.887 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #13: タンパク質 | 分子量: 29586.576 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() #14: タンパク質 | 分子量: 29512.807 Da / 分子数: 2 / 由来タイプ: 天然 / 由来: (天然) ![]() |
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-非ポリマー , 2種, 8分子 
| #15: 化合物 | ChemComp-A1L0D / [(~{ 分子量: 334.222 Da / 分子数: 6 / 由来タイプ: 合成 / 式: C16H27BN4O3 #16: 化合物 | |
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-詳細
| 研究の焦点であるリガンドがあるか | Y |
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| Has protein modification | Y |
-実験情報
-実験
| 実験 | 手法: 電子顕微鏡法 |
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| EM実験 | 試料の集合状態: PARTICLE / 3次元再構成法: 単粒子再構成法 |
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試料調製
| 構成要素 | 名称: 20S proteasome / タイプ: COMPLEX / Entity ID: #1-#14 / 由来: NATURAL |
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| 由来(天然) | 生物種: ![]() |
| 緩衝液 | pH: 7.5 |
| 試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: NO |
| 急速凍結 | 凍結剤: ETHANE |
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電子顕微鏡撮影
| 実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
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| 顕微鏡 | モデル: FEI TITAN KRIOS |
| 電子銃 | 電子線源: FIELD EMISSION GUN / 加速電圧: 300 kV / 照射モード: OTHER |
| 電子レンズ | モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 1600 nm / 最小 デフォーカス(公称値): 800 nm |
| 撮影 | 電子線照射量: 48.2 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
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解析
| EMソフトウェア | 名称: REFMAC |
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| CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
| 3次元再構成 | 解像度: 2.5 Å / 粒子像の数: 118136 / 対称性のタイプ: POINT |
| 精密化 | 最高解像度: 2.5 Å |
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FIELD EMISSION GUN