+データを開く
-基本情報
登録情報 | データベース: EMDB / ID: EMD-4146 | ||||||||||||
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タイトル | Human 26S proteasome in complex with Oprozomib | ||||||||||||
マップデータ | |||||||||||||
試料 |
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機能・相同性 | 機能・相同性情報 positive regulation of inclusion body assembly / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / thyrotropin-releasing hormone receptor binding / modulation by host of viral transcription / 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; オメガペプチターゼ / proteasome accessory complex / integrator complex / purine ribonucleoside triphosphate binding / meiosis I ...positive regulation of inclusion body assembly / Impaired BRCA2 translocation to the nucleus / Impaired BRCA2 binding to SEM1 (DSS1) / thyrotropin-releasing hormone receptor binding / modulation by host of viral transcription / 加水分解酵素; プロテアーゼ; ペプチド結合加水分解酵素; オメガペプチターゼ / proteasome accessory complex / integrator complex / purine ribonucleoside triphosphate binding / meiosis I / positive regulation of proteasomal protein catabolic process / proteasome regulatory particle / cytosolic proteasome complex / proteasome regulatory particle, lid subcomplex / proteasome-activating activity / proteasome regulatory particle, base subcomplex / protein K63-linked deubiquitination / metal-dependent deubiquitinase activity / regulation of endopeptidase activity / negative regulation of programmed cell death / Defective homologous recombination repair (HRR) due to BRCA1 loss of function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function / Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function / Homologous DNA Pairing and Strand Exchange / Regulation of ornithine decarboxylase (ODC) / Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA) / proteasome core complex / Resolution of D-loop Structures through Holliday Junction Intermediates / Cross-presentation of soluble exogenous antigens (endosomes) / Somitogenesis / K63-linked deubiquitinase activity / Impaired BRCA2 binding to RAD51 / immune system process / myofibril / proteasome binding / regulation of protein catabolic process / proteasome storage granule / Presynaptic phase of homologous DNA pairing and strand exchange / transcription factor binding / blastocyst development / general transcription initiation factor binding / NF-kappaB binding / endopeptidase activator activity / polyubiquitin modification-dependent protein binding / proteasome assembly / proteasome endopeptidase complex / positive regulation of RNA polymerase II transcription preinitiation complex assembly / proteasome core complex, beta-subunit complex / proteasome core complex, alpha-subunit complex / threonine-type endopeptidase activity / mRNA export from nucleus / enzyme regulator activity / regulation of proteasomal protein catabolic process / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / ERAD pathway / inclusion body / negative regulation of inflammatory response to antigenic stimulus / : / sarcomere / proteasome complex / Regulation of activated PAK-2p34 by proteasome mediated degradation / ciliary basal body / proteolysis involved in protein catabolic process / N-glycan trimming in the ER and Calnexin/Calreticulin cycle / Autodegradation of Cdh1 by Cdh1:APC/C / APC/C:Cdc20 mediated degradation of Securin / Asymmetric localization of PCP proteins / SCF-beta-TrCP mediated degradation of Emi1 / NIK-->noncanonical NF-kB signaling / Ubiquitin-dependent degradation of Cyclin D / AUF1 (hnRNP D0) binds and destabilizes mRNA / TNFR2 non-canonical NF-kB pathway / Vpu mediated degradation of CD4 / Assembly of the pre-replicative complex / Degradation of DVL / stem cell differentiation / CDK-mediated phosphorylation and removal of Cdc6 / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Dectin-1 mediated noncanonical NF-kB signaling / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / Hh mutants are degraded by ERAD / lipopolysaccharide binding / SCF(Skp2)-mediated degradation of p27/p21 / Degradation of AXIN / Degradation of GLI1 by the proteasome / Activation of NF-kappaB in B cells / Hedgehog ligand biogenesis / Defective CFTR causes cystic fibrosis / Negative regulation of NOTCH4 signaling / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / G2/M Checkpoints / Vif-mediated degradation of APOBEC3G / Autodegradation of the E3 ubiquitin ligase COP1 / Hedgehog 'on' state / Regulation of RUNX3 expression and activity / P-body / Degradation of GLI2 by the proteasome / GLI3 is processed to GLI3R by the proteasome / Orc1 removal from chromatin / double-strand break repair via homologous recombination 類似検索 - 分子機能 | ||||||||||||
生物種 | Homo sapiens (ヒト) / Synthetic construct (人工物) / Human (ヒト) | ||||||||||||
手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.8 Å | ||||||||||||
データ登録者 | Haselbach D / Schrader J / Lambrecht F / Henneberg F / Chari A / Stark H | ||||||||||||
資金援助 | ドイツ, 3件
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引用 | ジャーナル: Nat Commun / 年: 2017 タイトル: Long-range allosteric regulation of the human 26S proteasome by 20S proteasome-targeting cancer drugs. 著者: David Haselbach / Jil Schrader / Felix Lambrecht / Fabian Henneberg / Ashwin Chari / Holger Stark / 要旨: The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of ...The proteasome holoenzyme is the major non-lysosomal protease; its proteolytic activity is essential for cellular homeostasis. Thus, it is an attractive target for the development of chemotherapeutics. While the structural basis of core particle (CP) inhibitors is largely understood, their structural impact on the proteasome holoenzyme remains entirely elusive. Here, we determined the structure of the 26S proteasome with and without the inhibitor Oprozomib. Drug binding modifies the energy landscape of conformational motion in the proteasome regulatory particle (RP). Structurally, the energy barrier created by Oprozomib triggers a long-range allosteric regulation, resulting in the stabilization of a non-productive state. Thereby, the chemical drug-binding signal is converted, propagated and amplified into structural changes over a distance of more than 150 Å from the proteolytic site to the ubiquitin receptor Rpn10. The direct visualization of changes in conformational dynamics upon drug binding allows new ways to screen and develop future allosteric proteasome inhibitors. | ||||||||||||
履歴 |
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-構造の表示
ムービー |
ムービービューア |
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構造ビューア | EMマップ: SurfViewMolmilJmol/JSmol |
添付画像 |
-ダウンロードとリンク
-EMDBアーカイブ
マップデータ | emd_4146.map.gz | 13.9 MB | EMDBマップデータ形式 | |
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ヘッダ (付随情報) | emd-4146-v30.xml emd-4146.xml | 56.6 KB 56.6 KB | 表示 表示 | EMDBヘッダ |
画像 | emd_4146.png | 150.4 KB | ||
アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-4146 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-4146 | HTTPS FTP |
-検証レポート
文書・要旨 | emd_4146_validation.pdf.gz | 232.9 KB | 表示 | EMDB検証レポート |
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文書・詳細版 | emd_4146_full_validation.pdf.gz | 232 KB | 表示 | |
XML形式データ | emd_4146_validation.xml.gz | 6.7 KB | 表示 | |
アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-4146 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-4146 | HTTPS FTP |
-関連構造データ
関連構造データ | 5m32MC M: このマップから作成された原子モデル C: 同じ文献を引用 (文献) |
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類似構造データ | |
電子顕微鏡画像生データ | EMPIAR-10166 (タイトル: human 26S proteasome bound to the chemotherapeutic Oprozomib Data size: 100.5 Data #1: Particle stack of aligned, summed and dose weighted particle images from the human 26S proteasome bound to oprozomib. [picked particles - single frame - processed]) |
-リンク
EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
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「今月の分子」の関連する項目 |
-マップ
ファイル | ダウンロード / ファイル: emd_4146.map.gz / 形式: CCP4 / 大きさ: 144.7 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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ボクセルのサイズ | X=Y=Z: 1.27 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
密度 |
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対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
詳細 | EMDB XML:
CCP4マップ ヘッダ情報:
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-添付データ
-試料の構成要素
+全体 : human 26S proteasome in complex with oprozomib
+超分子 #1: human 26S proteasome in complex with oprozomib
+超分子 #2: human 26S proteasome
+超分子 #3: bound oprozomib
+分子 #1: Proteasome subunit alpha type-2
+分子 #2: Proteasome subunit alpha type-4
+分子 #3: Proteasome subunit alpha type-7
+分子 #4: Proteasome subunit alpha type-5
+分子 #5: Proteasome subunit alpha type-1
+分子 #6: Proteasome subunit alpha type-3
+分子 #7: Proteasome subunit alpha type-6
+分子 #8: Proteasome subunit beta type-7
+分子 #9: Proteasome subunit beta type-3
+分子 #10: Proteasome subunit beta type-2
+分子 #11: Proteasome subunit beta type-5
+分子 #12: Proteasome subunit beta type-1
+分子 #13: Proteasome subunit beta type-4
+分子 #14: Proteasome subunit beta type-6
+分子 #15: Proteasome subunit alpha type-7
+分子 #16: Proteasome subunit alpha type-1
+分子 #17: 26S protease regulatory subunit 7
+分子 #18: 26S protease regulatory subunit 4
+分子 #19: 26S protease regulatory subunit 6B
+分子 #20: 26S protease regulatory subunit 10B
+分子 #21: 26S protease regulatory subunit 6A
+分子 #22: 26S protease regulatory subunit 8
+分子 #23: 26S proteasome non-ATPase regulatory subunit 1
+分子 #24: 26S proteasome non-ATPase regulatory subunit 3
+分子 #25: 26S proteasome non-ATPase regulatory subunit 12
+分子 #26: 26S proteasome non-ATPase regulatory subunit 11
+分子 #27: 26S proteasome non-ATPase regulatory subunit 6
+分子 #28: 26S proteasome non-ATPase regulatory subunit 7
+分子 #29: 26S proteasome non-ATPase regulatory subunit 13
+分子 #30: 26S proteasome non-ATPase regulatory subunit 4
+分子 #31: 26S proteasome non-ATPase regulatory subunit 14
+分子 #32: 26S proteasome non-ATPase regulatory subunit 8
+分子 #33: 26S proteasome complex subunit SEM1
+分子 #34: bound Oprozomib
+分子 #35: ADENOSINE-5'-DIPHOSPHATE
-実験情報
-構造解析
手法 | クライオ電子顕微鏡法 |
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解析 | 単粒子再構成法 |
試料の集合状態 | particle |
-試料調製
緩衝液 | pH: 6.5 構成要素:
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グリッド | モデル: Quantifoil / 材質: COPPER / メッシュ: 200 / 支持フィルム - #0 - Film type ID: 1 / 支持フィルム - #0 - 材質: CARBON / 支持フィルム - #0 - トポロジー: HOLEY / 支持フィルム - #1 - Film type ID: 2 / 支持フィルム - #1 - 材質: CARBON / 支持フィルム - #1 - トポロジー: CONTINUOUS | ||||||||||||||||||
凍結 | 凍結剤: ETHANE / チャンバー内湿度: 72 % / チャンバー内温度: 4 K / 装置: LEICA EM GP / 詳細: blot with sensor. |
-電子顕微鏡法
顕微鏡 | FEI TITAN KRIOS |
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特殊光学系 | 球面収差補正装置: Microscope is equipped with Cs corrector |
撮影 | フィルム・検出器のモデル: FEI FALCON II (4k x 4k) 検出モード: OTHER / デジタル化 - サイズ - 横: 4096 pixel / デジタル化 - サイズ - 縦: 4096 pixel / デジタル化 - サンプリング間隔: 14.0 µm / 撮影したグリッド数: 1 / 平均露光時間: 1.0 sec. / 平均電子線量: 2.0 e/Å2 |
電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
電子光学系 | C2レンズ絞り径: 70.0 µm / 倍率(補正後): 110236 / 照射モード: SPOT SCAN / 撮影モード: BRIGHT FIELD / Cs: 0.0001 mm / 最大 デフォーカス(公称値): 8.4 µm / 最小 デフォーカス(公称値): 0.3 µm / 倍率(公称値): 59000 |
試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER ホルダー冷却材: NITROGEN |
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |