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

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Basic information

Entry
Database: PDB / ID: 9ogd
TitleCryo-EM structure of human exportin-1 conjugated with selinexor and bound to human ASB8(R197A)-ELOB/C
Components
  • Ankyrin repeat and SOCS box protein 8
  • Elongin-B
  • Elongin-C
  • Exportin-1
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 / annulate lamellae / regulation of proteasomal ubiquitin-dependent protein catabolic process / nuclear export signal receptor activity / Rev-mediated nuclear export of HIV RNA / target-directed miRNA degradation / elongin complex / NEP/NS2 Interacts with the Cellular Export Machinery ...cellular response to triglyceride / cellular response to salt / HuR (ELAVL1) binds and stabilizes mRNA / annulate lamellae / regulation of proteasomal ubiquitin-dependent protein catabolic process / nuclear export signal receptor activity / Rev-mediated nuclear export of HIV RNA / target-directed miRNA degradation / elongin complex / NEP/NS2 Interacts with the Cellular Export Machinery / nucleocytoplasmic transport / VCB complex / Cul5-RING ubiquitin ligase complex / ubiquitin-dependent protein catabolic process via the C-end degron rule pathway / Cul2-RING ubiquitin ligase complex / Maturation of DENV proteins / 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 / 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 / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / RHO GTPases Activate Formins / 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 / 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 / regulation of transcription by RNA polymerase II / ubiquitin protein ligase binding / nucleolus / 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 / 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 / SKP1/BTB/POZ domain superfamily / Ankyrin repeat profile. / Ankyrin repeats (3 copies) / Ankyrin repeat region circular profile. / ankyrin repeats / Ankyrin repeat / Ankyrin repeat-containing domain superfamily / Armadillo-like helical / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Armadillo-type fold / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
selinexor, bound form / Exportin-1 / Elongin-C / Elongin-B / Ankyrin repeat and SOCS box protein 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.49 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: Ankyrin repeat and SOCS box protein 8
E: Elongin-C
F: Elongin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,0135
Polymers177,5684
Non-polymers4451
Water00
1


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

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Components

#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 Ankyrin repeat and SOCS box protein 8 / ASB-8


Mass: 29783.045 Da / Num. of mol.: 1 / Fragment: residues 17-288 / Mutation: R197A
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
#3: 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
#4: 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
#5: 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
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

ComponentName: Ternary complex of full-length human XPO1 conjugated to KPT-185 and bound to ASB8(R197A)-ELOB/C
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightValue: 0.178 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Escherichia coli (E. coli) / Strain: BL21(DE3)
Buffer solutionpH: 7.4
Details: 20 mM HEPES pH 7.4, 110 mM KOAc, 2 mM Mg(OAc)2, 2 mM TCEP
SpecimenConc.: 0.8 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: C-flat-1.2/1.3
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: 165000 X / Nominal defocus max: 2400 nm / Nominal defocus min: 900 nm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 55 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 6256
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2SerialEMimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
8ISOLDEmodel fitting
9Cootmodel fitting
11PHENIXmodel refinement
12cryoSPARCinitial Euler assignment
13cryoSPARCfinal Euler assignment
14cryoSPARCclassification
15cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 3582585 / Details: blob picking followed by template picking
3D reconstructionResolution: 2.49 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 433178 / Symmetry type: POINT
Atomic model buildingB value: 102.26 / 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
ID 3D fitting-IDChain-IDDetails (eV)Source nameType
11Astarting model for XPO1 from final model of KPT-185-XPO1-ASB8-ELOB/C in this studyOtherexperimental model
21Bstarting model for ASB8 from final model of KPT-185-XPO1-ASB8-ELOB/C in this studyOtherexperimental model
31Estarting model for ELOC from final model of KPT-185-XPO1-ASB8-ELOB/C in this studyOtherexperimental model
41Fstarting model for ELOB from final model of KPT-185-XPO1-ASB8-ELOB/C in this studyOtherexperimental model
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00310181
ELECTRON MICROSCOPYf_angle_d0.45213804
ELECTRON MICROSCOPYf_dihedral_angle_d6.91348
ELECTRON MICROSCOPYf_chiral_restr0.0341585
ELECTRON MICROSCOPYf_plane_restr0.0041767

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