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- PDB-9ogb: Cryo-EM structure of human exportin-1 conjugated with selinexor a... -

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Entry
Database: PDB / ID: 9ogb
TitleCryo-EM structure of human exportin-1 conjugated with selinexor and bound to yeast RAN-GTP and human ASB8-ELOB/C
Components
  • Ankyrin repeat and SOCS box protein 8
  • Elongin-B
  • Elongin-C
  • Exportin-1
  • GTP-binding nuclear protein GSP1/CNR1
KeywordsPROTEIN TRANSPORT / nuclear export / inhibitor / protein degradation
Function / homology
Function and homology information


cellular response to triglyceride / cellular response to salt / HuR (ELAVL1) binds and stabilizes mRNA / regulation of nucleocytoplasmic transport / annulate lamellae / 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 / nucleus organization ...cellular response to triglyceride / cellular response to salt / HuR (ELAVL1) binds and stabilizes mRNA / regulation of nucleocytoplasmic transport / annulate lamellae / 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 / nucleus organization / target-directed miRNA degradation / Rev-mediated nuclear export of HIV RNA / elongin complex / NEP/NS2 Interacts with the Cellular Export Machinery / 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 / negative regulation of DNA-templated DNA replication / regulation of cell cycle phase transition / 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 / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / ribosomal large subunit export from nucleus / protein 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 / ribosome-associated ubiquitin-dependent protein catabolic process / 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 / protein import into nucleus / Resolution of Sister Chromatid Cohesion / transcription corepressor binding / Downregulation of TGF-beta receptor signaling / TP53 Regulates Transcription of DNA Repair Genes / Heme signaling / Maturation of DENV proteins / transcription initiation at RNA polymerase II promoter / RHO GTPases Activate Formins / transcription elongation by RNA polymerase II / Deactivation of the beta-catenin transactivating complex / 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 / Ribosome Quality Control (RQC) complex extracts and degrades nascent peptide / Separation of Sister Chromatids / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / nuclear envelope / nucleosome assembly / Antigen processing: Ubiquitination & Proteasome degradation / Neddylation / ribosome biogenesis / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / DNA-binding transcription factor binding / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-macromolecule adaptor activity / intracellular signal transduction / response to xenobiotic stimulus / protein ubiquitination / ribonucleoprotein complex / protein domain specific binding / ubiquitin protein ligase binding / GTPase activity / 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
Ankyrin repeat and SOCS box protein 8, SOCS box domain / SOCS box / SOCS box-like domain superfamily / SOCS box domain / SOCS box domain profile. / SOCS_box / Exportin-1, repeat 3 / Chromosome region maintenance repeat / Exportin-1, repeat 2 / Chromosome region maintenance or exportin repeat ...Ankyrin repeat and SOCS box protein 8, SOCS box domain / SOCS box / SOCS box-like domain superfamily / SOCS box domain / SOCS box domain profile. / SOCS_box / Exportin-1, repeat 3 / Chromosome region maintenance repeat / Exportin-1, repeat 2 / Chromosome region maintenance or exportin repeat / CRM1 / Exportin repeat 2 / CRM1 / Exportin repeat 3 / CRM1 C terminal / Exportin-1, C-terminal / CRM1 C terminal / Exportin-1/5 / Exportin-1/Importin-beta-like / Exportin 1-like protein / Ran GTPase / Small GTPase Ran-type domain profile. / Importin-beta N-terminal domain / Importin-beta N-terminal domain / Importin-beta N-terminal domain profile. / Importin-beta, N-terminal domain / Elongin-C / Elongin B / Ankyrin repeats (many copies) / S-phase kinase-associated protein 1-like / SKP1 component, POZ domain / Skp1 family, tetramerisation domain / Found in Skp1 protein family / Ran (Ras-related nuclear proteins) /TC4 subfamily of small GTPases / SKP1/BTB/POZ domain superfamily / Rho (Ras homology) subfamily of Ras-like small GTPases / Ras subfamily of RAS small GTPases / Small GTPase / Ras family / Ankyrin repeat profile. / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Rab subfamily of small GTPases / Ankyrin repeat-containing domain superfamily / Armadillo-like helical / Small GTP-binding protein domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Armadillo-type fold / Ubiquitin-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-TRIPHOSPHATE / selinexor, bound form / Exportin-1 / GTP-binding nuclear protein GSP1/CNR1 / Elongin-C / Elongin-B / Ankyrin repeat and SOCS box protein 8
Similarity search - Component
Biological speciesHomo sapiens (human)
Saccharomyces cerevisiae (brewer's yeast)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.25 Å
AuthorsWing, C.E. / Fung, H.Y.J. / Chook, Y.M.
Funding support United States, 7items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RP220582 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP180410 United States
Cancer Prevention and Research Institute of Texas (CPRIT)150053 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP170170 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM144137 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM131963 United States
Welch FoundationI-1532 United States
CitationJournal: Nat Chem Biol / Year: 2025
Title: 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.
History
DepositionApr 30, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 26, 2025Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Exportin-1
B: GTP-binding nuclear protein GSP1/CNR1
C: Ankyrin repeat and SOCS box protein 8
E: Elongin-C
F: Elongin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)199,2098
Polymers198,2165
Non-polymers9933
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 5 types, 5 molecules ABCEF

#1: Protein Exportin-1 / Exp1 / Chromosome region maintenance 1 protein homolog


Mass: 123662.484 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: GS remaining after TEV cleavage / Source: (gene. exp.) Homo sapiens (human) / Gene: XPO1, CRM1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O14980
#2: Protein GTP-binding nuclear protein GSP1/CNR1 / Chromosome stability protein 17 / GTPase Ran homolog / Genetic suppressor of PRP20-1


Mass: 20561.719 Da / Num. of mol.: 1 / Fragment: residues 1-179 / Mutation: Q71L
Source method: isolated from a genetically manipulated source
Details: GS remaining after TEV cleavage
Source: (gene. exp.) Saccharomyces cerevisiae (brewer's yeast)
Gene: GSP1, CNR1, CST17, YLR293C, L8003.19 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P32835
#3: Protein Ankyrin repeat and SOCS box protein 8 / ASB-8


Mass: 29869.162 Da / Num. of mol.: 1 / Fragment: residues 17-288
Source method: isolated from a genetically manipulated source
Details: GS remaining after TEV cleavage / Source: (gene. exp.) Homo sapiens (human) / Gene: ASB8, PP14212 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q9H765
#4: Protein Elongin-C / EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / ...EloC / Elongin 15 kDa subunit / RNA polymerase II transcription factor SIII subunit C / SIII p15 / Transcription elongation factor B polypeptide 1


Mass: 10974.616 Da / Num. of mol.: 1 / Fragment: residues 17-112
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: ELOC, TCEB1 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15369
#5: Protein Elongin-B / EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / ...EloB / Elongin 18 kDa subunit / RNA polymerase II transcription factor SIII subunit B / SIII p18 / Transcription elongation factor B polypeptide 2


Mass: 13147.781 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: full-length, wildtype / Source: (gene. exp.) Homo sapiens (human) / Gene: ELOB, TCEB2 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q15370

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Non-polymers , 3 types, 3 molecules

#6: Chemical ChemComp-V6A / selinexor, bound form / 3-{3-[3,5-bis(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}-N'-(pyrazin-2-yl)propanehydrazide


Mass: 445.322 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H13F6N7O / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-GTP / GUANOSINE-5'-TRIPHOSPHATE


Mass: 523.180 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H16N5O14P3 / Comment: GTP, energy-carrying molecule*YM
#8: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Quinary complex of full-length human XPO1 conjugated to selinexor and bound to RANGTP and ASB8-ELOB/CCOMPLEX#1-#50MULTIPLE SOURCES
2XPO1-ASB8-ELOB/CCOMPLEX#1, #3-#51RECOMBINANT
3RAN-GTPCOMPLEX#21RECOMBINANT
Molecular weightValue: 0.199 MDa / Experimental value: NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Saccharomyces cerevisiae (brewer's yeast)4932
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-IDStrain
22Escherichia coli (E. coli)469008BL21(DE3)
33Escherichia coli (E. coli)469008BL21(DE3)
Buffer solutionpH: 7.4
Details: 20 mM HEPES pH 7.4, 110 mM KOAc, 2 mM Mg(OAc)2, 2 mM TCEP
SpecimenConc.: 0.5 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 400 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 900 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 1 / Num. of real images: 4982
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 10 eV

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Processing

EM softwareName: PHENIX / Version: 1.19.1_4122: / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1821140 / Details: template picking followed by Topaz picking
3D reconstructionResolution: 3.25 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 78241 / Symmetry type: POINT
Atomic model buildingB value: 173.58 / Protocol: OTHER / Space: REAL
Details: Initial models were docked into maps using UCSF ChimeraX then manually built using Isolde and Coot and refined in PHENIX
Atomic model building

3D fitting-ID: 1 / Type: experimental model

IDPDB-IDPdb chain-IDChain-IDDetails (eV)Source nameAccession codeInitial refinement model-ID
1Bstarting model for ASB8 from final model of KPT-185-XPO1-ASB8-ELOB/C in this studyOther
2Estarting model for ELOC from final model of KPT-185-XPO1-ASB8-ELOB/C in this studyOther
3Fstarting model for ELOB from final model of KPT-185-XPO1-ASB8-ELOB/C in this studyOther
46TVO

6tvo

AAstarting model for XPO1, aligned to HEAT10-12 of XPO1-ASB8-ELOB/C from this studyPDB6TVO2
53M1I

3m1i

AAstarting model for yeast RAN, aligned to human RAN in 6TVOPDB3M1I3
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00313400
ELECTRON MICROSCOPYf_angle_d0.51418163
ELECTRON MICROSCOPYf_dihedral_angle_d6.5531772
ELECTRON MICROSCOPYf_chiral_restr0.0372071
ELECTRON MICROSCOPYf_plane_restr0.0032312

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