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Yorodumi- EMDB-70460: Cryo-EM structure of human exportin-1 conjugated with selinexor a... -
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Basic information
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| Title | Cryo-EM structure of human exportin-1 conjugated with selinexor and bound to yeast RAN-GTP and human ASB8-ELOB/C | ||||||||||||||||||||||||
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Keywords | nuclear export / inhibitor / protein degradation / PROTEIN TRANSPORT | ||||||||||||||||||||||||
| Function / homology | Function and homology informationcellular response to triglyceride / cellular response to salt / HuR (ELAVL1) binds and stabilizes mRNA / regulation of nucleocytoplasmic transport / annulate lamellae / regulation of cell cycle phase transition / exonucleolytic trimming to generate mature 3'-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / regulation of proteasomal ubiquitin-dependent protein catabolic process / Postmitotic nuclear pore complex (NPC) reformation / nuclear export signal receptor activity ...cellular response to triglyceride / cellular response to salt / HuR (ELAVL1) binds and stabilizes mRNA / regulation of nucleocytoplasmic transport / annulate lamellae / regulation of cell cycle phase transition / exonucleolytic trimming to generate mature 3'-end of 5.8S rRNA from tricistronic rRNA transcript (SSU-rRNA, 5.8S rRNA, LSU-rRNA) / regulation of proteasomal ubiquitin-dependent protein catabolic process / Postmitotic nuclear pore complex (NPC) reformation / nuclear export signal receptor activity / target-directed miRNA degradation / Rev-mediated nuclear export of HIV RNA / elongin complex / NEP/NS2 Interacts with the Cellular Export Machinery / nucleus organization / nucleocytoplasmic transport / VCB complex / Cul5-RING ubiquitin ligase complex / poly(A)+ mRNA export from nucleus / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul2-RING ubiquitin ligase complex / Maturation of hRSV A proteins / Maturation of DENV 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 / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / ribosomal large subunit export from nucleus / Tat-mediated elongation of the HIV-1 transcript / Cajal body / ribosomal subunit export from nucleus / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / mRNA 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 / NPAS4 regulates expression of target genes / protein export from nucleus / ribosomal small subunit export from nucleus / RNA Polymerase II Pre-transcription Events / Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal / Transcriptional and post-translational regulation of MITF-M expression and activity / Mitotic Prometaphase / EML4 and NUDC in mitotic spindle formation / Resolution of Sister Chromatid Cohesion / transcription corepressor binding / Downregulation of TGF-beta receptor signaling / TP53 Regulates Transcription of DNA Repair Genes / Heme signaling / Deactivation of the beta-catenin transactivating complex / protein import into nucleus / transcription initiation at RNA polymerase II promoter / RHO GTPases Activate Formins / transcription elongation by RNA polymerase II / Inactivation of CSF3 (G-CSF) signaling / Vif-mediated degradation of APOBEC3G / MAPK6/MAPK4 signaling / Evasion by RSV of host interferon responses / Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha / small GTPase binding / kinetochore / Regulation of expression of SLITs and ROBOs / Separation of Sister Chromatids / nuclear envelope / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / nucleosome assembly / Antigen processing: Ubiquitination & Proteasome degradation / Neddylation / ribosome biogenesis / protein-containing complex assembly / DNA-binding transcription factor binding / ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / intracellular signal transduction / response to xenobiotic stimulus / protein ubiquitination / ribonucleoprotein complex / protein domain specific binding / GTPase activity / ubiquitin protein ligase binding / regulation of transcription by RNA polymerase II / nucleolus / GTP binding / negative regulation of transcription by RNA polymerase II / protein-containing complex / RNA binding / nucleoplasm / membrane / nucleus / cytosol / cytoplasm Similarity search - Function | ||||||||||||||||||||||||
| Biological species | Homo sapiens (human) / ![]() | ||||||||||||||||||||||||
| Method | single particle reconstruction / cryo EM / Resolution: 3.25 Å | ||||||||||||||||||||||||
Authors | Wing CE / Fung HYJ / Chook YM | ||||||||||||||||||||||||
| Funding support | United States, 7 items
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Citation | Journal: Nat Chem Biol / Year: 2025Title: SINE compounds activate exportin 1 degradation through an allosteric mechanism. Authors: Casey E Wing / Ho Yee Joyce Fung / Bert Kwanten / Tolga Cagatay / Ashley B Niesman / Maarten Jacquemyn / Mehdi Gharghabi / Brecht Permentier / Binita Shakya / Rhituparna Nandi / Joseph M ...Authors: Casey E 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 / ![]() Abstract: Overexpression of exportin 1 (XPO1/CRM1) in cancer cells mislocalizes numerous cancer-related nuclear export cargoes. Covalent selective inhibitors of nuclear export (SINEs), including the cancer ...Overexpression of exportin 1 (XPO1/CRM1) in cancer cells mislocalizes numerous cancer-related nuclear export cargoes. Covalent selective inhibitors of nuclear export (SINEs), including the cancer drug selinexor, restore proper nuclear localization by blocking XPO1-cargo interaction. These inhibitors also induce XPO1 degradation through the Cullin-RING E3 ligase (CRL) substrate receptor ASB8. Here we present cryo-electron microscopy structures revealing ASB8 binding to a cryptic XPO1 site that is exposed upon SINE conjugation. Unlike typical molecular glue degraders that directly bridge CRLs and substrates, SINEs bind XPO1 independently of ASB8, triggering an allosteric mechanism that enables high-affinity ASB8 recruitment, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also triggered by the endogenous itaconate derivative 4-octyl itaconate, suggesting that synthetic XPO1 inhibitors exploit a native cellular mechanism. This allosteric XPO1 degradation mechanism expands known modes of targeted protein degradation beyond molecular glue degraders and proteolysis-targeting chimeras of CRL4. | ||||||||||||||||||||||||
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Structure visualization
| Supplemental images |
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Downloads & links
-EMDB archive
| Map data | emd_70460.map.gz | 122.1 MB | EMDB map data format | |
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| Header (meta data) | emd-70460-v30.xml emd-70460.xml | 32.8 KB 32.8 KB | Display Display | EMDB header |
| FSC (resolution estimation) | emd_70460_fsc.xml | 13.2 KB | Display | FSC data file |
| Images | emd_70460.png | 49.8 KB | ||
| Filedesc metadata | emd-70460.cif.gz | 9.1 KB | ||
| Others | emd_70460_half_map_1.map.gz emd_70460_half_map_2.map.gz | 226.9 MB 226.9 MB | ||
| Archive directory | http://ftp.pdbj.org/pub/emdb/structures/EMD-70460 ftp://ftp.pdbj.org/pub/emdb/structures/EMD-70460 | HTTPS FTP |
-Related structure data
| Related structure data | ![]() 9ogbMC ![]() 9og9C ![]() 9ogaC ![]() 9ogcC ![]() 9ogdC ![]() 9ogeC ![]() 9ogfC ![]() 9ognC ![]() 9ogoC M: atomic model generated by this map C: citing same article ( |
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| Similar structure data | Similarity search - Function & homology F&H Search |
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Links
| EMDB pages | EMDB (EBI/PDBe) / EMDataResource |
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| Related items in Molecule of the Month |
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Map
| File | Download / File: emd_70460.map.gz / Format: CCP4 / Size: 244.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES) | ||||||||||||||||||||||||||||||||||||
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| Projections & slices | Image control
Images are generated by Spider. | ||||||||||||||||||||||||||||||||||||
| Voxel size | X=Y=Z: 0.834 Å | ||||||||||||||||||||||||||||||||||||
| Density |
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| Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||
| Details | EMDB XML:
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-Supplemental data
-Half map: #2
| File | emd_70460_half_map_1.map | ||||||||||||
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| Density Histograms |
-Half map: #1
| File | emd_70460_half_map_2.map | ||||||||||||
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| Density Histograms |
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Sample components
+Entire : Quinary complex of full-length human XPO1 conjugated to selinexor...
+Supramolecule #1: Quinary complex of full-length human XPO1 conjugated to selinexor...
+Supramolecule #2: XPO1-ASB8-ELOB/C
+Supramolecule #3: RAN-GTP
+Macromolecule #1: Exportin-1
+Macromolecule #2: GTP-binding nuclear protein GSP1/CNR1
+Macromolecule #3: Ankyrin repeat and SOCS box protein 8
+Macromolecule #4: Elongin-C
+Macromolecule #5: Elongin-B
+Macromolecule #6: selinexor, bound form
+Macromolecule #7: GUANOSINE-5'-TRIPHOSPHATE
+Macromolecule #8: MAGNESIUM ION
-Experimental details
-Structure determination
| Method | cryo EM |
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Processing | single particle reconstruction |
| Aggregation state | particle |
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Sample preparation
| Concentration | 0.5 mg/mL |
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| Buffer | pH: 7.4 Details: 20 mM HEPES pH 7.4, 110 mM KOAc, 2 mM Mg(OAc)2, 2 mM TCEP |
| Grid | Model: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 400 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 80 sec. |
| Vitrification | Cryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
| Microscope | TFS KRIOS |
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| Specialist optics | Energy filter - Name: GIF Bioquantum / Energy filter - Slit width: 10 eV |
| Image recording | Film or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 4982 / Average electron dose: 60.0 e/Å2 |
| Electron beam | Acceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN |
| Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.9 µm / Nominal magnification: 105000 |
| Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
| Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
-Atomic model buiding 1
| Initial model |
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| Details | Initial models were docked into maps using UCSF ChimeraX then manually built using Isolde and Coot and refined in PHENIX | ||||||||||||||||||
| Refinement | Space: REAL / Protocol: OTHER / Overall B value: 173.58 | ||||||||||||||||||
| Output model | ![]() PDB-9ogb: |
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About Yorodumi



Keywords
Homo sapiens (human)
Authors
United States, 7 items
Citation

































Z (Sec.)
Y (Row.)
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FIELD EMISSION GUN



