+データを開く
-基本情報
登録情報 | データベース: PDB / ID: 8roy | ||||||
---|---|---|---|---|---|---|---|
タイトル | Structure of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound to compound furan 24 | ||||||
要素 |
| ||||||
キーワード | LIGASE (リガーゼ) / E3 ligase (ユビキチンリガーゼ) / Complex | ||||||
機能・相同性 | 機能・相同性情報 regulation of natural killer cell activation / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex ...regulation of natural killer cell activation / positive regulation by virus of viral protein levels in host cell / epigenetic programming in the zygotic pronuclei / spindle assembly involved in female meiosis / Cul4-RING E3 ubiquitin ligase complex / UV-damage excision repair / biological process involved in interaction with symbiont / regulation of mitotic cell cycle phase transition / WD40-repeat domain binding / Cul4A-RING E3 ubiquitin ligase complex / Cul4B-RING E3 ubiquitin ligase complex / ubiquitin ligase complex scaffold activity / immune system process / negative regulation of reproductive process / negative regulation of developmental process / cullin family protein binding / small molecule binding / viral release from host cell / ectopic germ cell programmed cell death / positive regulation of viral genome replication / positive regulation of gluconeogenesis / proteasomal protein catabolic process / nucleotide-excision repair / Recognition of DNA damage by PCNA-containing replication complex / DNA Damage Recognition in GG-NER / regulation of circadian rhythm / Dual Incision in GG-NER / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / Wntシグナル経路 / Formation of Incision Complex in GG-NER / protein polyubiquitination / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / positive regulation of protein catabolic process / cellular response to UV / rhythmic process / protein-macromolecule adaptor activity / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / site of double-strand break / Neddylation / ubiquitin-dependent protein catabolic process / proteasome-mediated ubiquitin-dependent protein catabolic process / chromosome, telomeric region / damaged DNA binding / protein ubiquitination / DNA修復 / apoptotic process / DNA damage response / protein-containing complex binding / 核小体 / negative regulation of apoptotic process / protein-containing complex / DNA binding / extracellular space / extracellular exosome / 核質 / metal ion binding / 細胞核 / 細胞質 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: 3.1 Å | ||||||
データ登録者 | Shilliday, F. / Lucas, S.C.C. / Richter, M. / Michaelides, I.N. / Fusani, L. | ||||||
資金援助 | 1件
| ||||||
引用 | ジャーナル: J Med Chem / 年: 2024 タイトル: Optimization of Potent Ligands for the E3 Ligase DCAF15 and Evaluation of Their Use in Heterobifunctional Degraders. 著者: Simon C C Lucas / Afshan Ahmed / S Neha Ashraf / Argyrides Argyrou / Matthias R Bauer / Gian Marco De Donatis / Sylvain Demanze / Frederik Eisele / Lucia Fusani / Andreas Hock / Ganesh ...著者: Simon C C Lucas / Afshan Ahmed / S Neha Ashraf / Argyrides Argyrou / Matthias R Bauer / Gian Marco De Donatis / Sylvain Demanze / Frederik Eisele / Lucia Fusani / Andreas Hock / Ganesh Kadamur / Shuyou Li / Abigail Macmillan-Jones / Iacovos N Michaelides / Christopher Phillips / Marie Rehnström / Magdalena Richter / Monica C Rodrigo-Brenni / Fiona Shilliday / Peng Wang / R Ian Storer / 要旨: Unlocking novel E3 ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on the current suite of ligands used to recruit E3 ...Unlocking novel E3 ligases for use in heterobifunctional PROTAC degraders is of high importance to the pharmaceutical industry. Over-reliance on the current suite of ligands used to recruit E3 ligases could limit the potential of their application. To address this, potent ligands for DCAF15 were optimized using cryo-EM supported, structure-based design to improve on micromolar starting points. A potent binder, compound , was identified and subsequently conjugated into PROTACs against multiple targets. Following attempts on degrading a number of proteins using DCAF15 recruiting PROTACs, only degradation of BRD4 was observed. Deconvolution of the mechanism of action showed that this degradation was not mediated by DCAF15, thereby highlighting both the challenges faced when trying to expand the toolbox of validated E3 ligase ligands for use in PROTAC degraders and the pitfalls of using BRD4 as a model substrate. | ||||||
履歴 |
|
-構造の表示
構造ビューア | 分子: MolmilJmol/JSmol |
---|
-ダウンロードとリンク
-ダウンロード
PDBx/mmCIF形式 | 8roy.cif.gz | 243.3 KB | 表示 | PDBx/mmCIF形式 |
---|---|---|---|---|
PDB形式 | pdb8roy.ent.gz | 表示 | PDB形式 | |
PDBx/mmJSON形式 | 8roy.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/ro/8roy ftp://data.pdbj.org/pub/pdb/validation_reports/ro/8roy | HTTPS FTP |
---|
-関連構造データ
関連構造データ | 19407MC 8roxC 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 (文献) |
---|---|
類似構造データ | 類似検索 - 機能・相同性F&H 検索 |
-リンク
-集合体
登録構造単位 |
|
---|---|
1 |
|
-要素
#1: タンパク質 | 分子量: 66822.609 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: DCAF15, C19orf72 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: Q66K64 |
---|---|
#2: タンパク質 | 分子量: 93347.078 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: DDB1, XAP1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: Q16531 |
#3: タンパク質 | 分子量: 11855.297 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: DDA1, C19orf58, PCIA1 発現宿主: Spodoptera frugiperda (ツマジロクサヨトウ) 参照: UniProt: Q9BW61 |
#4: 化合物 | ChemComp-A1H18 / 分子量: 513.394 Da / 分子数: 1 / 由来タイプ: 合成 / 式: C21H22Cl2N4O5S / タイプ: SUBJECT OF INVESTIGATION |
研究の焦点であるリガンドがあるか | Y |
-実験情報
-実験
実験 | 手法: 電子顕微鏡法 |
---|---|
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 | 名称: Complex of the human DDB1-DDA1-DCAF15 E3 ubiquitin ligase bound to compound furan 24 タイプ: COMPLEX / Entity ID: #1-#3 / 由来: RECOMBINANT |
---|---|
由来(天然) | 生物種: Homo sapiens (ヒト) |
由来(組換発現) | 生物種: Spodoptera frugiperda (ツマジロクサヨトウ) |
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 |
-電子顕微鏡撮影
実験機器 | モデル: Titan Krios / 画像提供: FEI Company |
---|---|
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 / 最大 デフォーカス(公称値): 3000 nm / 最小 デフォーカス(公称値): 500 nm |
撮影 | 電子線照射量: 60 e/Å2 フィルム・検出器のモデル: GATAN K3 BIOQUANTUM (6k x 4k) |
-解析
EMソフトウェア | 名称: PHENIX / バージョン: 1.21rc1_5084: / カテゴリ: モデル精密化 | ||||||||||||||||||||||||
---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
CTF補正 | タイプ: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
3次元再構成 | 解像度: 3.1 Å / 解像度の算出法: FSC 0.143 CUT-OFF / 粒子像の数: 405189 / 対称性のタイプ: POINT | ||||||||||||||||||||||||
拘束条件 |
|