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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: 9q03 | ||||||
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タイトル | Cryo-EM structure of ternary complex BCL6-CRBN-DDB1 with BCL6-760 (LDD, local refined) | ||||||
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![]() | LIGASE / Cereblon / BCL6 / LDD / degrader / E3 | ||||||
機能・相同性 | ![]() negative regulation of monoatomic ion transmembrane transport / regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation ...negative regulation of monoatomic ion transmembrane transport / regulation of memory T cell differentiation / negative regulation of mitotic cell cycle DNA replication / intronic transcription regulatory region sequence-specific DNA binding / negative regulation of isotype switching to IgE isotypes / negative regulation of plasma cell differentiation / negative regulation of T-helper 2 cell differentiation / isotype switching to IgE isotypes / negative regulation of mast cell cytokine production / regulation of germinal center formation / negative regulation of mononuclear cell proliferation / plasma cell differentiation / paraspeckles / germinal center formation / regulation of immune system process / pyramidal neuron differentiation / type 2 immune response / T-helper 2 cell differentiation / positive regulation of regulatory T cell differentiation / positive regulation of cell motility / negative regulation of B cell apoptotic process / Cul4A-RING E3 ubiquitin ligase complex / negative regulation of Rho protein signal transduction / erythrocyte development / FOXO-mediated transcription of cell death genes / locomotory exploration behavior / regulation of cell differentiation / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / regulation of T cell proliferation / B cell proliferation / negative regulation of cellular senescence / negative regulation of cell-matrix adhesion / negative regulation of Notch signaling pathway / positive regulation of Wnt signaling pathway / regulation of immune response / negative regulation of protein-containing complex assembly / Rho protein signal transduction / positive regulation of B cell proliferation / positive regulation of neuron differentiation / regulation of cytokine production / cell-matrix adhesion / transcription corepressor binding / positive regulation of protein-containing complex assembly / cell motility / negative regulation of cell growth / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / cell morphogenesis / sequence-specific double-stranded DNA binding / intracellular protein localization / heterochromatin formation / regulation of cell population proliferation / actin cytoskeleton organization / regulation of inflammatory response / Interleukin-4 and Interleukin-13 signaling / spermatogenesis / DNA-binding transcription factor binding / sequence-specific DNA binding / Potential therapeutics for SARS / proteasome-mediated ubiquitin-dependent protein catabolic process / transmembrane transporter binding / transcription by RNA polymerase II / protein ubiquitination / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / inflammatory response / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / nucleolus / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / Golgi apparatus / zinc ion binding / nucleoplasm / metal ion binding / identical protein binding / nucleus / membrane / 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 / クライオ電子顕微鏡法 / 解像度: 3.15 Å | ||||||
![]() | Zhu, J. / Fang, W. / Pagarigan, B. | ||||||
資金援助 | 1件
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![]() | ![]() タイトル: Discovery of Potent and Selective BCL6 Ligand-Directed Degrader (LDD), BCL6-760. 著者: Hunter P Shunatona / Natalie Holmberg Douglas / Jayce Rhodes / William Thomas / Diogo Da Silva / Jim Gamez / Matt Groza / Andy Christoforou / Jinyi Zhu / Scott Johnson / Dharmpal Dodd / Dehua ...著者: Hunter P Shunatona / Natalie Holmberg Douglas / Jayce Rhodes / William Thomas / Diogo Da Silva / Jim Gamez / Matt Groza / Andy Christoforou / Jinyi Zhu / Scott Johnson / Dharmpal Dodd / Dehua Huang / Jennifer Griffin / Giulianna Miseo / Brandon Whitefield / Dahlia Weiss / James Rader / Elif Kuzu / Jim Leisten / Joselyn Del Rosario / Lihong Shi / Mary Matyskiela / Philip P Chamberlain / Peter Belmont / Matt Alexander / Christoph W Zapf / Lynda Groocock / Deborah S Mortensen / ![]() 要旨: The discovery of a potent and selective BCL6 ligand-directed degrader (LDD), BCL6-760 () is described. Through structure-activity relationships, the most potent heterobifunctional degraders of BCL6 ...The discovery of a potent and selective BCL6 ligand-directed degrader (LDD), BCL6-760 () is described. Through structure-activity relationships, the most potent heterobifunctional degraders of BCL6 were found to be those containing short aminopiperidine linkers in combination with an indazole-based cereblon (CRBN)-binding moiety (CBM). In vitro ADME profiling of potent molecules identified BCL6-760 as an ideal molecule for use in in vivo experiments due to its good passive permeability, solubility, and microsomal stability. Mechanistic studies confirmed that BCL6 degradation is CRBN mediated, and proteomic assessment indicates a clean and selective degradation profile. BCL6-760 exhibited good oral mouse PK and was capable of penetrant and sustained PD effects. At 60 mg/kg BID dosing, BCL6-760 achieves >90% BCL6 reduction and leads to an overall 64% tumor volume reduction in an OCI-LY-1 mouse xenograft efficacy model. | ||||||
履歴 |
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Remark 650 | HELIX DETERMINATION METHOD: MOE | ||||||
Remark 700 | SHEET DETERMINATION METHOD: MOE |
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構造の表示
構造ビューア | 分子: ![]() ![]() |
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ダウンロードとリンク
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ダウンロード
PDBx/mmCIF形式 | ![]() | 234.4 KB | 表示 | ![]() |
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PDB形式 | ![]() | 表示 | ![]() | |
PDBx/mmJSON形式 | ![]() | ツリー表示 | ![]() | |
その他 | ![]() |
-検証レポート
文書・要旨 | ![]() | 1.4 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.4 MB | 表示 | |
XML形式データ | ![]() | 31.8 KB | 表示 | |
CIF形式データ | ![]() | 46.5 KB | 表示 | |
アーカイブディレクトリ | ![]() ![]() | HTTPS FTP |
-関連構造データ
関連構造データ | ![]() 72086MC M: このデータのモデリングに利用したマップデータ C: 同じ文献を引用 ( |
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類似構造データ | 類似検索 - 機能・相同性 ![]() |
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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
#1: タンパク質 | 分子量: 16431.863 Da / 分子数: 2 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() ![]() #2: タンパク質 | | 分子量: 53581.984 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() 発現宿主: ![]() ![]() 参照: UniProt: Q96SW2 #3: 化合物 | ChemComp-ZN / | #4: 化合物 | ChemComp-A1CM7 / ( | 分子量: 715.244 Da / 分子数: 1 / 由来タイプ: 合成 / 式: C36H43ClN10O4 / タイプ: SUBJECT OF INVESTIGATION 研究の焦点であるリガンドがあるか | Y | Has protein modification | N | 非ポリマーの詳細 | LIG DICTIONARY 94 100 Other LIG C1 C1 C 0 YNN 1 LIG C10 C10 C 0 YNN 2 LIG C11 C11 C 0 YNN 3 LIG C12 ...LIG DICTIONARY | |
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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 |
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試料調製
構成要素 | 名称: ternary complex of BCL6-CRBN-DDB1 with an LDD BCL6-760 タイプ: COMPLEX 詳細: BCL6 BTB domain and CRBN/DDB1 was mixed with BCL6-760 in 1:1:1 ratio Entity ID: #1-#2 / 由来: RECOMBINANT | ||||||||||||||||||||||||||||||
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分子量 | 値: 0.162 MDa / 実験値: NO | ||||||||||||||||||||||||||||||
由来(天然) | 生物種: ![]() | ||||||||||||||||||||||||||||||
由来(組換発現) | 生物種: ![]() ![]() | ||||||||||||||||||||||||||||||
緩衝液 | pH: 7 | ||||||||||||||||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 4 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES | ||||||||||||||||||||||||||||||
試料支持 | グリッドの材料: GOLD / グリッドのサイズ: 300 divisions/in. / グリッドのタイプ: Quantifoil R1.2/1.3 | ||||||||||||||||||||||||||||||
急速凍結 | 装置: FEI VITROBOT MARK IV / 凍結剤: ETHANE / 湿度: 100 % / 凍結前の試料温度: 278 K |
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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: TFS 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): 1800 nm / 最小 デフォーカス(公称値): 1200 nm / Cs: 2.7 mm / アライメント法: COMA FREE |
試料ホルダ | 凍結剤: NITROGEN 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
撮影 | 平均露光時間: 3.16 sec. / 電子線照射量: 35.18 e/Å2 フィルム・検出器のモデル: TFS FALCON 4i (4k x 4k) 撮影したグリッド数: 1 / 実像数: 10236 |
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解析
EMソフトウェア |
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CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 15859703 | |||||||||||||||||||||||||||
対称性 | 点対称性: C1 (非対称) | |||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.15 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 112568 / アルゴリズム: FOURIER SPACE / クラス平均像の数: 1 / 対称性のタイプ: POINT | |||||||||||||||||||||||||||
原子モデル構築 | プロトコル: RIGID BODY FIT / 空間: REAL | |||||||||||||||||||||||||||
原子モデル構築 |
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精密化 | 最高解像度: 3.15 Å |