+
データを開く
-
基本情報
| 登録情報 | ![]() | ||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| タイトル | Cryo-EM structure of human exportin-1 conjugated with selinexor and bound to yeast RAN-GTP and human ASB8-ELOB/C | ||||||||||||||||||||||||
マップデータ | |||||||||||||||||||||||||
試料 |
| ||||||||||||||||||||||||
キーワード | nuclear export / inhibitor / protein degradation / PROTEIN TRANSPORT | ||||||||||||||||||||||||
| 機能・相同性 | 機能・相同性情報cellular response to triglyceride / cellular response to salt / regulation of cell cycle phase transition / HuR (ELAVL1) binds and stabilizes mRNA / annulate lamellae / regulation of nucleocytoplasmic transport / exonucleolytic trimming to generate mature 3'-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / Postmitotic nuclear pore complex (NPC) reformation / regulation of proteasomal ubiquitin-dependent protein catabolic process / nuclear export signal receptor activity ...cellular response to triglyceride / cellular response to salt / regulation of cell cycle phase transition / HuR (ELAVL1) binds and stabilizes mRNA / annulate lamellae / regulation of nucleocytoplasmic transport / exonucleolytic trimming to generate mature 3'-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / Postmitotic nuclear pore complex (NPC) reformation / regulation of proteasomal ubiquitin-dependent protein catabolic process / nuclear export signal receptor activity / regulation of centrosome duplication / regulation of protein export from nucleus / target-directed miRNA degradation / elongin complex / Rev-mediated nuclear export of HIV RNA / NEP/NS2 Interacts with the Cellular Export Machinery / VCB complex / nucleocytoplasmic transport / Cul5-RING ubiquitin ligase complex / poly(A)+ mRNA export from nucleus / Cul2-RING ubiquitin ligase complex / nucleus organization / Maturation of hRSV A proteins / 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 / ribosomal large subunit export from nucleus / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / protein localization to nucleus / Tat-mediated elongation of the HIV-1 transcript / mRNA export from nucleus / Formation of HIV-1 elongation complex containing HIV-1 Tat / Cajal body / Formation of HIV elongation complex in the absence of HIV Tat / ribosomal subunit export from nucleus / Cyclin A/B1/B2 associated events during G2/M transition / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / ribosomal small subunit export from nucleus / NPAS4 regulates expression of target genes / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / RNA Polymerase II Pre-transcription Events / Transcriptional and post-translational regulation of MITF-M expression and activity / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / protein export from nucleus / Resolution of Sister Chromatid Cohesion / Downregulation of TGF-beta receptor signaling / transcription corepressor binding / TP53 Regulates Transcription of DNA Repair Genes / Deactivation of the beta-catenin transactivating complex / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / Heme signaling / RHO GTPases Activate Formins / Vif-mediated degradation of APOBEC3G / MAPK6/MAPK4 signaling / Inactivation of CSF3 (G-CSF) signaling / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / kinetochore / Evasion by RSV of host interferon responses / small GTPase binding / Regulation of expression of SLITs and ROBOs / protein import into nucleus / Separation of Sister Chromatids / nuclear envelope / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / ribosome biogenesis / Neddylation / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / nuclear membrane / protein-macromolecule adaptor activity / DNA-binding transcription factor binding / intracellular signal transduction / protein ubiquitination / response to xenobiotic stimulus / ribonucleoprotein complex / protein domain specific binding / intracellular membrane-bounded organelle / GTPase activity / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / GTP binding / nucleolus / negative regulation of transcription by RNA polymerase II / protein-containing complex / RNA binding / nucleoplasm / nucleus / membrane / cytosol / cytoplasm 類似検索 - 分子機能 | ||||||||||||||||||||||||
| 生物種 | Homo sapiens (ヒト) / ![]() | ||||||||||||||||||||||||
| 手法 | 単粒子再構成法 / クライオ電子顕微鏡法 / 解像度: 3.25 Å | ||||||||||||||||||||||||
データ登録者 | Wing CE / Fung HYJ / Chook YM | ||||||||||||||||||||||||
| 資金援助 | 米国, 7件
| ||||||||||||||||||||||||
引用 | ジャーナル: bioRxiv / 年: 2025タイトル: SINE compounds activate exportin-1 degradation via an allosteric mechanism. 著者: Casey Elizabeth Wing / Ho Yee Joyce Fung / Bert Kwanten / Tolga Cagatay / Ashley B Niesman / Maarten Jacquemyn / Mehdi Gharghabi / Brecht Permentier / Binita Shakya / Rhituparna Nandi / ...著者: Casey Elizabeth Wing / Ho Yee Joyce Fung / Bert Kwanten / Tolga Cagatay / Ashley B Niesman / Maarten Jacquemyn / Mehdi Gharghabi / Brecht Permentier / Binita Shakya / Rhituparna Nandi / Joseph M Ready / Trinayan Kashyap / Sharon Shacham / Yosef Landesman / Rosa Lapalombella / Dirk Daelemans / Yuh Min Chook 要旨: The nuclear export receptor exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells, leading to the mislocalization of numerous cancer-related protein cargoes . Selinexor, a covalent XPO1 ...The nuclear export receptor exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells, leading to the mislocalization of numerous cancer-related protein cargoes . Selinexor, a covalent XPO1 inhibitor, and other Selective Inhibitor of Nuclear Export (SINEs) restore proper nuclear localization by blocking XPO1-cargo binding . SINEs also induce XPO1 degradation via the Cullin-RING E3 ubiquitin ligase (CRL) substrate receptor ASB8 . Here we elucidate the mechanism underlying the high-affinity engagement of CRL5 with SINE-conjugated XPO1. Cryogenic electron microscopy (cryoEM) structures reveal that ASB8 binds to a cryptic site on XPO1, which becomes accessible only upon SINE conjugation. While molecular glue degraders typically interact with both CRL and the substrate , SINEs bind to XPO1 without requiring interaction with ASB8 for efficient XPO1 degradation. Instead, an allosteric mechanism facilitates high affinity XPO1-ASB8 interaction, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also observed upon treatment of the endogenous itaconate derivate 4-octyl itaconate, which suggests a native mechanism that is inadvertently exploited by synthesized XPO1 inhibitors. This allosteric XPO1 degradation mechanism of SINE compounds expands the known modes of targeted protein degradation beyond the well-characterized molecular glue degraders and proteolysis targeting chimeras of CRL4. | ||||||||||||||||||||||||
| 履歴 |
|
-
構造の表示
| 添付画像 |
|---|
-
ダウンロードとリンク
-EMDBアーカイブ
| マップデータ | emd_70460.map.gz | 122.1 MB | EMDBマップデータ形式 | |
|---|---|---|---|---|
| ヘッダ (付随情報) | emd-70460-v30.xml emd-70460.xml | 31.3 KB 31.3 KB | 表示 表示 | EMDBヘッダ |
| FSC (解像度算出) | emd_70460_fsc.xml | 13.2 KB | 表示 | FSCデータファイル |
| 画像 | emd_70460.png | 49.8 KB | ||
| Filedesc metadata | emd-70460.cif.gz | 8.8 KB | ||
| その他 | emd_70460_half_map_1.map.gz emd_70460_half_map_2.map.gz | 226.9 MB 226.9 MB | ||
| アーカイブディレクトリ | http://ftp.pdbj.org/pub/emdb/structures/EMD-70460 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-70460 | HTTPS FTP |
-検証レポート
| 文書・要旨 | emd_70460_validation.pdf.gz | 1003.7 KB | 表示 | EMDB検証レポート |
|---|---|---|---|---|
| 文書・詳細版 | emd_70460_full_validation.pdf.gz | 1003.3 KB | 表示 | |
| XML形式データ | emd_70460_validation.xml.gz | 21.3 KB | 表示 | |
| CIF形式データ | emd_70460_validation.cif.gz | 26.7 KB | 表示 | |
| アーカイブディレクトリ | https://ftp.pdbj.org/pub/emdb/validation_reports/EMD-70460 ftp://ftp.pdbj.org/pub/emdb/validation_reports/EMD-70460 | HTTPS FTP |
-関連構造データ
| 関連構造データ | ![]() 9ogbMC ![]() 9og9C ![]() 9ogaC ![]() 9ogcC ![]() 9ogdC ![]() 9ogeC ![]() 9ogfC ![]() 9ognC ![]() 9ogoC M: このマップから作成された原子モデル C: 同じ文献を引用 ( |
|---|---|
| 類似構造データ | 類似検索 - 機能・相同性 F&H 検索 |
-
リンク
| EMDBのページ | EMDB (EBI/PDBe) / EMDataResource |
|---|---|
| 「今月の分子」の関連する項目 |
-
マップ
| ファイル | ダウンロード / ファイル: emd_70460.map.gz / 形式: CCP4 / 大きさ: 244.1 MB / タイプ: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 投影像・断面図 | 画像のコントロール
画像は Spider により作成 | ||||||||||||||||||||||||||||||||||||
| ボクセルのサイズ | X=Y=Z: 0.834 Å | ||||||||||||||||||||||||||||||||||||
| 密度 |
| ||||||||||||||||||||||||||||||||||||
| 対称性 | 空間群: 1 | ||||||||||||||||||||||||||||||||||||
| 詳細 | EMDB XML:
|
-添付データ
-ハーフマップ: #2
| ファイル | emd_70460_half_map_1.map | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 投影像・断面図 |
| ||||||||||||
| 密度ヒストグラム |
-ハーフマップ: #1
| ファイル | emd_70460_half_map_2.map | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 投影像・断面図 |
| ||||||||||||
| 密度ヒストグラム |
-
試料の構成要素
+全体 : Quinary complex of full-length human XPO1 conjugated to selinexor...
+超分子 #1: Quinary complex of full-length human XPO1 conjugated to selinexor...
+超分子 #2: XPO1-ASB8-ELOB/C
+超分子 #3: RAN-GTP
+分子 #1: Exportin-1
+分子 #2: GTP-binding nuclear protein GSP1/CNR1
+分子 #3: Ankyrin repeat and SOCS box protein 8
+分子 #4: Elongin-C
+分子 #5: Elongin-B
+分子 #6: selinexor, bound form
+分子 #7: GUANOSINE-5'-TRIPHOSPHATE
+分子 #8: MAGNESIUM ION
-実験情報
-構造解析
| 手法 | クライオ電子顕微鏡法 |
|---|---|
解析 | 単粒子再構成法 |
| 試料の集合状態 | particle |
-
試料調製
| 濃度 | 0.5 mg/mL |
|---|---|
| 緩衝液 | pH: 7.4 詳細: 20 mM HEPES pH 7.4, 110 mM KOAc, 2 mM Mg(OAc)2, 2 mM TCEP |
| グリッド | モデル: Quantifoil R1.2/1.3 / 材質: COPPER / メッシュ: 400 / 前処理 - タイプ: GLOW DISCHARGE / 前処理 - 時間: 80 sec. |
| 凍結 | 凍結剤: ETHANE / チャンバー内湿度: 95 % / チャンバー内温度: 277 K / 装置: FEI VITROBOT MARK IV |
-
電子顕微鏡法
| 顕微鏡 | TFS KRIOS |
|---|---|
| 特殊光学系 | 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: 10 eV |
| 撮影 | フィルム・検出器のモデル: GATAN K3 (6k x 4k) / 撮影したグリッド数: 1 / 実像数: 4982 / 平均電子線量: 60.0 e/Å2 |
| 電子線 | 加速電圧: 300 kV / 電子線源: FIELD EMISSION GUN |
| 電子光学系 | 照射モード: FLOOD BEAM / 撮影モード: BRIGHT FIELD / 最大 デフォーカス(公称値): 2.4 µm / 最小 デフォーカス(公称値): 0.9 µm / 倍率(公称値): 105000 |
| 試料ステージ | 試料ホルダーモデル: FEI TITAN KRIOS AUTOGRID HOLDER |
| 実験機器 | ![]() モデル: Titan Krios / 画像提供: FEI Company |
+
画像解析
-原子モデル構築 1
| 初期モデル |
| ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 詳細 | Initial models were docked into maps using UCSF ChimeraX then manually built using Isolde and Coot and refined in PHENIX | ||||||||||||||||||
| 精密化 | 空間: REAL / プロトコル: OTHER / 温度因子: 173.58 | ||||||||||||||||||
| 得られたモデル | ![]() PDB-9ogb: |
ムービー
コントローラー
万見について




キーワード
Homo sapiens (ヒト)
データ登録者
米国, 7件
引用
































Z (Sec.)
Y (Row.)
X (Col.)







































FIELD EMISSION GUN



