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基本情報
登録情報 | データベース: PDB / ID: 6xmx | |||||||||||||||
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タイトル | Cryo-EM structure of BCL6 bound to BI-3802 | |||||||||||||||
![]() | B-cell lymphoma 6 protein | |||||||||||||||
![]() | TRANSCRIPTION / transcription factor / degrader | |||||||||||||||
機能・相同性 | ![]() 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 ...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 / pyramidal neuron differentiation / regulation of immune system process / type 2 immune response / positive regulation of regulatory T cell differentiation / T-helper 2 cell differentiation / negative regulation of B cell apoptotic process / positive regulation of cell motility / negative regulation of Rho protein signal transduction / FOXO-mediated transcription of cell death genes / negative regulation of cell-matrix adhesion / regulation of T cell proliferation / negative regulation of Notch signaling pathway / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / B cell proliferation / regulation of cell differentiation / negative regulation of cellular senescence / Rho protein signal transduction / regulation of immune response / erythrocyte development / heterochromatin formation / positive regulation of B cell proliferation / regulation of cytokine production / positive regulation of neuron differentiation / cell-matrix adhesion / transcription corepressor binding / cell motility / cell morphogenesis / protein localization / negative regulation of cell growth / chromatin DNA binding / DNA-binding transcription repressor activity, RNA polymerase II-specific / sequence-specific double-stranded DNA binding / regulation of cell population proliferation / regulation of inflammatory response / actin cytoskeleton organization / spermatogenesis / Interleukin-4 and Interleukin-13 signaling / DNA-binding transcription factor binding / sequence-specific DNA binding / transcription by RNA polymerase II / inflammatory response / positive regulation of apoptotic process / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / negative regulation of DNA-templated transcription / DNA damage response / chromatin binding / nucleolus / Golgi apparatus / negative regulation of transcription by RNA polymerase II / nucleoplasm / identical protein binding / nucleus / metal ion binding 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: 3.7 Å | |||||||||||||||
![]() | Yoon, H. / Burman, S.S.R. / Hunkeler, M. / Nowak, R.P. / Fischer, E.S. | |||||||||||||||
資金援助 | ![]() ![]()
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![]() | ![]() タイトル: Small-molecule-induced polymerization triggers degradation of BCL6. 著者: Mikołaj Słabicki / Hojong Yoon / Jonas Koeppel / Lena Nitsch / Shourya S Roy Burman / Cristina Di Genua / Katherine A Donovan / Adam S Sperling / Moritz Hunkeler / Jonathan M Tsai / Rohan ...著者: Mikołaj Słabicki / Hojong Yoon / Jonas Koeppel / Lena Nitsch / Shourya S Roy Burman / Cristina Di Genua / Katherine A Donovan / Adam S Sperling / Moritz Hunkeler / Jonathan M Tsai / Rohan Sharma / Andrew Guirguis / Charles Zou / Priya Chudasama / Jessica A Gasser / Peter G Miller / Claudia Scholl / Stefan Fröhling / Radosław P Nowak / Eric S Fischer / Benjamin L Ebert / ![]() ![]() 要旨: Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy ...Effective and sustained inhibition of non-enzymatic oncogenic driver proteins is a major pharmacological challenge. The clinical success of thalidomide analogues demonstrates the therapeutic efficacy of drug-induced degradation of transcription factors and other cancer targets, but a substantial subset of proteins are resistant to targeted degradation using existing approaches. Here we report an alternative mechanism of targeted protein degradation, in which a small molecule induces the highly specific, reversible polymerization of a target protein, followed by its sequestration into cellular foci and subsequent degradation. BI-3802 is a small molecule that binds to the Broad-complex, Tramtrack and Bric-à-brac (BTB) domain of the oncogenic transcription factor B cell lymphoma 6 (BCL6) and leads to the proteasomal degradation of BCL6. We use cryo-electron microscopy to reveal how the solvent-exposed moiety of a BCL6-binding molecule contributes to a composite ligand-protein surface that engages BCL6 homodimers to form a supramolecular structure. Drug-induced formation of BCL6 filaments facilitates ubiquitination by the SIAH1 E3 ubiquitin ligase. Our findings demonstrate that a small molecule such as BI-3802 can induce polymerization coupled to highly specific protein degradation, which in the case of BCL6 leads to increased pharmacological activity compared to the effects induced by other BCL6 inhibitors. These findings open new avenues for the development of therapeutic agents and synthetic biology. | |||||||||||||||
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構造の表示
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構造ビューア | 分子: ![]() ![]() |
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PDBx/mmCIF形式 | ![]() | 377.5 KB | 表示 | ![]() |
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PDB形式 | ![]() | 291.7 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 | ![]() | 1.6 MB | 表示 | ![]() |
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文書・詳細版 | ![]() | 1.7 MB | 表示 | |
XML形式データ | ![]() | 43.8 KB | 表示 | |
CIF形式データ | ![]() | 58.4 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
#1: タンパク質 | 分子量: 44505.305 Da / 分子数: 8 / 変異: R160C / 由来タイプ: 組換発現 / 由来: (組換発現) ![]() ![]() #2: 化合物 | ChemComp-U52 / 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: FILAMENT / 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: B-cell lymphoma 6 protein (BCL6) filament / タイプ: ORGANELLE OR CELLULAR COMPONENT 詳細: BCL6 polymerized upon addition of small molecule BI-3802. 4 dimers enclosed in map. Entity ID: #1 / 由来: RECOMBINANT | ||||||||||||||||||||
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分子量 | 値: 0.352 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: 7.4 | ||||||||||||||||||||
緩衝液成分 |
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試料 | 濃度: 0.48 mg/ml / 包埋: NO / シャドウイング: NO / 染色: NO / 凍結: YES 詳細: Strep II-Avi BCL6 (aa5-360) polymerized by addition of 1.5 molar excess BI-3802. CHAPSO (0.8 mM final) added for grid preparation. | ||||||||||||||||||||
試料支持 | グリッドの材料: COPPER / 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: LEICA EM GP / 凍結剤: ETHANE / 湿度: 95 % / 凍結前の試料温度: 283.15 K / 詳細: 4 ul sample applied twice, blotted 1.3s each time |
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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 詳細: Data collection in counting mode, using multi shot scheme (4 holes per stage position, 2 shots per hole) |
電子銃 | 電子線源: ![]() |
電子レンズ | モード: BRIGHT FIELD / 倍率(公称値): 105000 X / 最大 デフォーカス(公称値): -2500 nm / 最小 デフォーカス(公称値): -1000 nm / Cs: 2.7 mm / C2レンズ絞り径: 50 µm / 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 sec. / 電子線照射量: 63.4 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) 撮影したグリッド数: 1 / 実像数: 7553 |
電子光学装置 | エネルギーフィルター名称: GIF Bioquantum / エネルギーフィルタースリット幅: 20 eV |
画像スキャン | 横: 5760 / 縦: 4092 |
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解析
ソフトウェア |
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EMソフトウェア |
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画像処理 | 詳細: The selected movies were corrected for beam-induced motion. | ||||||||||||||||||||||||||||||||||||||||||||
CTF補正 | 詳細: Standard CTF correction in relion, based on parameters estimated by CTFFIND4 タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||||||||||||||||||||||
粒子像の選択 | 選択した粒子像数: 1610413 / 詳細: particles picked with crYOLO | ||||||||||||||||||||||||||||||||||||||||||||
対称性 | 点対称性: C1 (非対称) | ||||||||||||||||||||||||||||||||||||||||||||
3次元再構成 | 解像度: 3.7 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 112048 / 詳細: as implemented in Relion / 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 詳細: Real_space_refine: global minimization, rigid body and adp refinement with target restraints. | ||||||||||||||||||||||||||||||||||||||||||||
原子モデル構築 | PDB-ID: 5MW2 PDB chain-ID: A / Accession code: 5MW2 / Pdb chain residue range: 7-128 / Source name: PDB / タイプ: experimental model | ||||||||||||||||||||||||||||||||||||||||||||
精密化 | 交差検証法: NONE 立体化学のターゲット値: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||||||||||||||||||||||
原子変位パラメータ | Biso mean: 23.38 Å2 | ||||||||||||||||||||||||||||||||||||||||||||
拘束条件 |
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