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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: 8q7r | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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タイトル | Ubiquitin ligation to substrate by a cullin-RING E3 ligase & Cdc34: NEDD8-CUL2-RBX1-ELOB/C-FEM1C with trapped UBE2R2~donor UB-Sil1 peptide | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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![]() | LIGASE / CUL2 / FEM1C / ELOBC / SIL1 / Ubiquitin / Ubiquitin Ligase / Ubiquitylation / monoubiquitylation / Elongin B / Elongin C | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
機能・相同性 | ![]() adenyl-nucleotide exchange factor activity / cotranslational protein targeting to membrane / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling ...adenyl-nucleotide exchange factor activity / cotranslational protein targeting to membrane / cullin-RING-type E3 NEDD8 transferase / NEDD8 transferase activity / cullin-RING ubiquitin ligase complex / cellular response to chemical stress / Cul7-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / target-directed miRNA degradation / Loss of Function of FBXW7 in Cancer and NOTCH1 Signaling / VCB complex / elongin complex / positive regulation of protein autoubiquitination / protein neddylation / NEDD8 ligase activity / negative regulation of response to oxidative stress / Cul5-RING ubiquitin ligase complex / SCF ubiquitin ligase complex / Cul2-RING ubiquitin ligase complex / ubiquitin-ubiquitin ligase activity / negative regulation of type I interferon production / Cul4A-RING E3 ubiquitin ligase complex / SCF-dependent proteasomal ubiquitin-dependent protein catabolic process / E2 ubiquitin-conjugating enzyme / Cul3-RING ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / negative regulation of mitophagy / Prolactin receptor signaling / ubiquitin conjugating enzyme activity / cullin family protein binding / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / protein monoubiquitination / ubiquitin ligase complex / Tat-mediated elongation of the HIV-1 transcript / ubiquitin-like ligase-substrate adaptor activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / protein K48-linked ubiquitination / Formation of HIV elongation complex in the absence of HIV Tat / RNA Polymerase II Transcription Elongation / Nuclear events stimulated by ALK signaling in cancer / Formation of RNA Pol II elongation complex / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / RNA Polymerase II Pre-transcription Events / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / regulation of cellular response to insulin stimulus / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / positive regulation of TORC1 signaling / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / Negative regulation of FLT3 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / Constitutive Signaling by NOTCH1 HD Domain Mutants / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / post-translational protein modification / APC-Cdc20 mediated degradation of Nek2A / p75NTR recruits signalling complexes / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Regulation of pyruvate metabolism / intrinsic apoptotic signaling pathway / Regulation of innate immune responses to cytosolic DNA / negative regulation of insulin receptor signaling pathway / NF-kB is activated and signals survival / Downregulation of ERBB2:ERBB3 signaling / Pexophagy / NRIF signals cell death from the nucleus / VLDLR internalisation and degradation / Regulation of PTEN localization / Activated NOTCH1 Transmits Signal to the Nucleus / Synthesis of active ubiquitin: roles of E1 and E2 enzymes / Regulation of BACH1 activity / T cell activation / MAP3K8 (TPL2)-dependent MAPK1/3 activation / TICAM1, RIP1-mediated IKK complex recruitment / Translesion synthesis by REV1 / Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE) / Translesion synthesis by POLK / InlB-mediated entry of Listeria monocytogenes into host cell / Downregulation of TGF-beta receptor signaling 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 / クライオ電子顕微鏡法 / 解像度: 3.71 Å | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
![]() | Liwocha, J. / Prabu, J.R. / Kleiger, G. / Schulman, B.A. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
資金援助 | ![]()
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![]() | ![]() 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: ![]() ![]() |
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ダウンロード
PDBx/mmCIF形式 | ![]() | 323.6 KB | 表示 | ![]() |
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PDB形式 | ![]() | 240.2 KB | 表示 | ![]() |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.1 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.2 MB | 表示 | |
XML形式データ | ![]() | 63.3 KB | 表示 | |
CIF形式データ | ![]() | 96.6 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-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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要素
-タンパク質 , 7種, 7分子 AHUCDGR
#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) ![]() ![]() |
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#2: タンパク質 | 分子量: 68767.312 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
#3: タンパク質 | 分子量: 77146.438 Da / 分子数: 1 / 由来タイプ: 組換発現 詳細: ...詳細: MQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGMQIFVKTLTGKTITLEVEPSDTIENVKAKIQDKEGIPPDQQRLIFAGKQLEDGRTLSDYNIQKESTLHLVLRLRGGV 由来: (組換発現) ![]() ![]() ![]() |
#5: タンパク質 | 分子量: 27190.932 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
#6: 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) ![]() ![]() ![]() |
#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) ![]() ![]() ![]() |
#8: タンパク質 | 分子量: 12289.977 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() 参照: UniProt: P62877, RING-type E3 ubiquitin transferase, cullin-RING-type E3 NEDD8 transferase |
-タンパク質・ペプチド , 1種, 1分子 F
#4: タンパク質・ペプチド | 分子量: 2227.457 Da / 分子数: 1 / Mutation: D442C S455P L456T L457Q K458G E459R L460A / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() |
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-非ポリマー , 2種, 4分子 
#9: 化合物 | ChemComp-U9O / 分子量: 117.146 Da / 分子数: 1 / 由来タイプ: 合成 / 式: C5H11NO2 |
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#10: 化合物 |
-詳細
研究の焦点であるリガンドがあるか | N |
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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 |
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分子量 | 値: 0.18 MDa / 実験値: NO | ||||||||||||||||||||||||
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 |
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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: ![]() |
電子レンズ | モード: BRIGHT FIELD / 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) |
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解析
EMソフトウェア | 名称: PHENIX / カテゴリ: モデル精密化 |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION |
対称性 | 点対称性: C1 (非対称) |
3次元再構成 | 解像度: 3.71 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 135564 / 対称性のタイプ: POINT |