+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8r5h | ||||||
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タイトル | Ubiquitin ligation to neosubstrate by a cullin-RING E3 ligase & Cdc34: NEDD8-CUL2-RBX1-ELOB/C-VHL-MZ1 with trapped UBE2R2~donor UB-BRD4 BD2 | ||||||
要素 |
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キーワード | LIGASE (リガーゼ) / CUL2 / VHL / ELOBC / BRD4 (BRD4) / MZ1 / PROTAC (タンパク質分解誘導キメラ分子) / Ubiquitin (ユビキチン) / Ubiquitin Ligase (ユビキチンリガーゼ) / Monoubiquitylation / NEDD8 / RBX1 | ||||||
機能・相同性 | 機能・相同性情報 regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway ...regulation of cellular response to hypoxia / cullin-RING-type E3 NEDD8 transferase / cellular response to chemical stress / NEDD8 transferase activity / RHOBTB3 ATPase cycle / cullin-RING ubiquitin ligase complex / negative regulation of receptor signaling pathway via JAK-STAT / transcription elongation factor activity / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / target-directed miRNA degradation / elongin complex / VCB complex / positive regulation of protein autoubiquitination / protein neddylation / Replication of the SARS-CoV-1 genome / NEDD8 ligase activity / Cul5-RING ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / Cul4A-RING E3 ubiquitin ligase complex / SCF複合体 / Cul2-RING ubiquitin ligase complex / negative regulation of type I interferon production / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / ユビキチン結合酵素 / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / Cul3-RING ubiquitin ligase complex / intracellular non-membrane-bounded organelle / SUMOylation of ubiquitinylation proteins / Prolactin receptor signaling / negative regulation of transcription elongation by RNA polymerase II / protein monoubiquitination / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / ubiquitin conjugating enzyme activity / cullin family protein binding / RNA polymerase II C-terminal domain binding / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / negative regulation of DNA damage checkpoint / P-TEFb complex binding / ubiquitin-like ligase-substrate adaptor activity / negative regulation by host of viral transcription / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Nuclear events stimulated by ALK signaling in cancer / protein K48-linked ubiquitination / Formation of HIV elongation complex in the absence of HIV Tat / negative regulation of signal transduction / positive regulation of T-helper 17 cell lineage commitment / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / グリコーゲン合成 / negative regulation of TORC1 signaling / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / positive regulation of TORC1 signaling / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1-dependent activation of IRF3/IRF7 / RNA Polymerase II Pre-transcription Events / APC/C:Cdc20 mediated degradation of Cyclin B / positive regulation of G2/M transition of mitotic cell cycle / p75NTR recruits signalling complexes / Downregulation of ERBB4 signaling / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / T細胞 / PINK1-PRKN Mediated Mitophagy / histone reader activity / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Pexophagy / Regulation of innate immune responses to cytosolic DNA / VLDLR internalisation and degradation / InlA-mediated entry of Listeria monocytogenes into host cells / Downregulation of ERBB2:ERBB3 signaling / NF-kB is activated and signals survival / NRIF signals cell death from the nucleus / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Regulation of BACH1 activity / Translesion synthesis by REV1 / Synthesis of active ubiquitin: roles of E1 and E2 enzymes 類似検索 - 分子機能 | ||||||
生物種 | Homo sapiens (ヒト) | ||||||
手法 | 電子顕微鏡法 / 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.44 Å | ||||||
データ登録者 | Liwocha, J. / Prabu, J.R. / Kleiger, G. / Schulman, B.A. | ||||||
資金援助 | ドイツ, 1件
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引用 | ジャーナル: Mol Cell / 年: 2024 タイトル: Cullin-RING ligases employ geometrically optimized catalytic partners for substrate targeting. 著者: Jerry Li / Nicholas Purser / Joanna Liwocha / Daniel C Scott / Holly A Byers / Barbara Steigenberger / Spencer Hill / Ishita Tripathi-Giesgen / Trent Hinkle / Fynn M Hansen / J Rajan Prabu / ...著者: Jerry Li / Nicholas Purser / Joanna Liwocha / Daniel C Scott / Holly A Byers / Barbara Steigenberger / Spencer Hill / Ishita Tripathi-Giesgen / Trent Hinkle / Fynn M Hansen / J Rajan Prabu / Senthil K Radhakrishnan / Donald S Kirkpatrick / Kurt M Reichermeier / Brenda A Schulman / Gary Kleiger / 要旨: Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. ...Cullin-RING ligases (CRLs) ubiquitylate specific substrates selected from other cellular proteins. Substrate discrimination and ubiquitin transferase activity were thought to be strictly separated. Substrates are recognized by substrate receptors, such as Fbox or BCbox proteins. Meanwhile, CRLs employ assorted ubiquitin-carrying enzymes (UCEs, which are a collection of E2 and ARIH-family E3s) specialized for either initial substrate ubiquitylation (priming) or forging poly-ubiquitin chains. We discovered specific human CRL-UCE pairings governing substrate priming. The results reveal pairing of CUL2-based CRLs and UBE2R-family UCEs in cells, essential for efficient PROTAC-induced neo-substrate degradation. Despite UBE2R2's intrinsic programming to catalyze poly-ubiquitylation, CUL2 employs this UCE for geometrically precise PROTAC-dependent ubiquitylation of a neo-substrate and for rapid priming of substrates recruited to diverse receptors. Cryo-EM structures illuminate how CUL2-based CRLs engage UBE2R2 to activate substrate ubiquitylation. Thus, pairing with a specific UCE overcomes E2 catalytic limitations to drive substrate ubiquitylation and targeted protein degradation. | ||||||
履歴 |
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-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
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-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8r5h.cif.gz | 274.8 KB | 表示 | PDBx/mmCIF形式 |
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PDB形式 | pdb8r5h.ent.gz | 210.8 KB | 表示 | PDB形式 |
PDBx/mmJSON形式 | 8r5h.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/r5/8r5h ftp://data.pdbj.org/pub/pdb/validation_reports/r5/8r5h | HTTPS FTP |
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-関連構造データ
-リンク
-集合体
登録構造単位 |
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1 |
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-要素
-タンパク質 , 8種, 8分子 ARCUDFGH
#1: タンパク質 | 分子量: 87098.930 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: CUL2 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: Q13617 |
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#2: タンパク質 | 分子量: 11945.547 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: RBX1, RNF75, ROC1 / 発現宿主: Trichoplusia ni (イラクサキンウワバ) / 参照: UniProt: P62877 |
#3: タンパク質 | 分子量: 25853.664 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: UBE2R2, CDC34B, UBC3B / 発現宿主: Escherichia coli BL21 (大腸菌) / 参照: UniProt: Q712K3, ユビキチン結合酵素 |
#4: タンパク質 | 分子量: 8519.778 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: UBC / 発現宿主: Escherichia coli BL21 (大腸菌) / 参照: UniProt: P0CG48 |
#5: タンパク質 | 分子量: 12485.135 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: ELOC, TCEB1 / 発現宿主: Escherichia coli BL21 (大腸菌) / 参照: UniProt: Q15369 |
#6: タンパク質 | 分子量: 13256.254 Da / 分子数: 1 / Mutation: C356A C357A K368C C391A C429A / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: BRD4, HUNK1 / 発現宿主: Escherichia coli BL21 (大腸菌) / 参照: UniProt: O60885 |
#7: タンパク質 | 分子量: 13147.781 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: ELOB, TCEB2 / 発現宿主: Escherichia coli BL21 (大腸菌) / 参照: UniProt: Q15370 |
#8: タンパク質 | 分子量: 18558.162 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 遺伝子: VHL / 発現宿主: Escherichia coli BL21 (大腸菌) / 参照: UniProt: P40337 |
-非ポリマー , 3種, 5分子
#9: 化合物 | #10: 化合物 | ChemComp-SY8 / | #11: 化合物 | ChemComp-759 / ( | |
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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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-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 |
-試料調製
構成要素 |
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分子量 |
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由来(天然) |
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由来(組換発現) |
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緩衝液 | pH: 7.5 | ||||||||||||||||||||||||
試料 | 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||
急速凍結 | 凍結剤: ETHANE-PROPANE |
-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: FLOOD BEAM |
電子レンズ | モード: BRIGHT FIELDBright-field microscopy / 倍率(公称値): 130000 X / 最大 デフォーカス(公称値): 2600 nm / 最小 デフォーカス(公称値): 600 nm |
撮影 | 電子線照射量: 66 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
-解析
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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対称性 | 点対称性: C1 (非対称) | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.44 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 148402 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
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