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- EMDB-70459: Cryo-EM structure of human full-length XPO1 conjugated with selinexor -

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Basic information

Entry
Database: EMDB / ID: EMD-70459
TitleCryo-EM structure of human full-length XPO1 conjugated with selinexor
Map data
Sample
  • Complex: Human wildtype full-length exportin-1 (XPO1) covalently bound to selinexor
    • Protein or peptide: Exportin-1
  • Ligand: selinexor, bound form
Keywordsnuclear export / HEAT repeat / inhibitor / PROTEIN TRANSPORT
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 / NEP/NS2 Interacts with the Cellular Export Machinery / nucleocytoplasmic transport / Maturation of DENV proteins ...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 / NEP/NS2 Interacts with the Cellular Export Machinery / nucleocytoplasmic transport / Maturation of DENV proteins / Maturation of hRSV A proteins / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / ribosomal large subunit export from nucleus / Cajal body / ribosomal subunit export from nucleus / mRNA export from nucleus / Cyclin A/B1/B2 associated events during G2/M transition / NPAS4 regulates expression of target genes / protein export from nucleus / ribosomal small subunit export from nucleus / 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 / Downregulation of TGF-beta receptor signaling / Heme signaling / Deactivation of the beta-catenin transactivating complex / RHO GTPases Activate Formins / MAPK6/MAPK4 signaling / small GTPase binding / kinetochore / Separation of Sister Chromatids / nuclear envelope / ribosome biogenesis / DNA-binding transcription factor binding / response to xenobiotic stimulus / ribonucleoprotein complex / protein domain specific binding / nucleolus / negative regulation of transcription by RNA polymerase II / protein-containing complex / RNA binding / nucleoplasm / membrane / nucleus / cytosol / cytoplasm
Similarity search - Function
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, 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 / Armadillo-like helical / Armadillo-type fold
Similarity search - Domain/homology
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.37 Å
AuthorsWing CE / Fung HYJ / Chook YM
Funding support United States, 7 items
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)RP150053 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, 2025-
Header (metadata) releaseNov 26, 2025-
Map releaseNov 26, 2025-
UpdateJul 22, 2026-
Current statusJul 22, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70459.png

Downloads & links

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Map

FileDownload / File: emd_70459.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.83 Å/pix.
x 280 pix.
= 231.28 Å		0.83 Å/pix.
x 280 pix.
= 231.28 Å		0.83 Å/pix.
x 280 pix.
= 231.28 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.826 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0586
Minimum - Maximum-0.18121992 - 0.3709248
Average (Standard dev.)0.0001813418 (±0.01080407)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 231.28 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_70459_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_70459_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human wildtype full-length exportin-1 (XPO1) covalently bound to ...

EntireName: Human wildtype full-length exportin-1 (XPO1) covalently bound to selinexor
Components
  • Complex: Human wildtype full-length exportin-1 (XPO1) covalently bound to selinexor
    • Protein or peptide: Exportin-1
  • Ligand: selinexor, bound form

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Supramolecule #1: Human wildtype full-length exportin-1 (XPO1) covalently bound to ...

SupramoleculeName: Human wildtype full-length exportin-1 (XPO1) covalently bound to selinexor
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 124 KDa

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Macromolecule #1: Exportin-1

MacromoleculeName: Exportin-1 / type: protein_or_peptide / ID: 1
Details: GS remaining after TEV cleavage, covalently bound to selinexor at C528
Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 123.662484 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: GSMPAIMTML ADHAARQLLD FSQKLDINLL DNVVNCLYHG EGAQQRMAQE VLTHLKEHPD AWTRVDTILE FSQNMNTKYY GLQILENVI KTRWKILPRN QCEGIKKYVV GLIIKTSSDP TCVEKEKVYI GKLNMILVQI LKQEWPKHWP TFISDIVGAS R TSESLCQN ...String:
GSMPAIMTML ADHAARQLLD FSQKLDINLL DNVVNCLYHG EGAQQRMAQE VLTHLKEHPD AWTRVDTILE FSQNMNTKYY GLQILENVI KTRWKILPRN QCEGIKKYVV GLIIKTSSDP TCVEKEKVYI GKLNMILVQI LKQEWPKHWP TFISDIVGAS R TSESLCQN NMVILKLLSE EVFDFSSGQI TQVKSKHLKD SMCNEFSQIF QLCQFVMENS QNAPLVHATL ETLLRFLNWI PL GYIFETK LISTLIYKFL NVPMFRNVSL KCLTEIAGVS VSQYEEQFVT LFTLTMMQLK QMLPLNTNIR LAYSNGKDDE QNF IQNLSL FLCTFLKEHD QLIEKRLNLR ETLMEALHYM LLVSEVEETE IFKICLEYWN HLAAELYRES PFSTSASPLL SGSQ HFDVP PRRQLYLPML FKVRLLMVSR MAKPEEVLVV ENDQGEVVRE FMKDTDSINL YKNMRETLVY LTHLDYVDTE RIMTE KLHN QVNGTEWSWK NLNTLCWAIG SISGAMHEED EKRFLVTVIK DLLGLCEQKR GKDNKAIIAS NIMYIVGQYP RFLRAH WKF LKTVVNKLFE FMHETHDGVQ DMACDTFIKI AQKCRRHFVQ VQVGEVMPFI DEILNNINTI ICDLQPQQVH TFYEAVG YM IGAQTDQTVQ EHLIEKYMLL PNQVWDSIIQ QATKNVDILK DPETVKQLGS ILKTNVRACK AVGHPFVIQL GRIYLDML N VYKCLSENIS AAIQANGEMV TKQPLIRSMR TVKRETLKLI SGWVSRSNDP QMVAENFVPP LLDAVLIDYQ RNVPAAREP EVLSTMAIIV NKLGGHITAE IPQIFDAVFE CTLNMINKDF EEYPEHRTNF FLLLQAVNSH CFPAFLAIPP TQFKLVLDSI IWAFKHTMR NVADTGLQIL FTLLQNVAQE EAAAQSFYQT YFCDILQHIF SVVTDTSHTA GLTMHASILA YMFNLVEEGK I STSLNPGN PVNNQIFLQE YVANLLKSAF PHLQDAQVKL FVTGLFSLNQ DIPAFKEHLR DFLVQIKEFA GEDTSDLFLE ER EIALRQA DEEKHKRQMS VPGIFNPHEI PEEMCD

UniProtKB: Exportin-1

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Macromolecule #2: selinexor, bound form

MacromoleculeName: selinexor, bound form / type: ligand / ID: 2 / Number of copies: 1 / Formula: V6A
Molecular weightTheoretical: 445.322 Da
Chemical component information

ChemComp-V6A:
selinexor, bound form

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3 mg/mL
BufferpH: 7.4
Details: 20 mM HEPES pH 7.4, 110 mM KOAc, 2 mM Mg(OAc)2, 2 mM TCEP
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 300 / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 80 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 95 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: GIF Bioquantum / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Number grids imaged: 1 / Number real images: 5852 / Average electron dose: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.9 µm / Nominal magnification: 105000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Particle selectionNumber selected: 1197263
Details: template picking using unliganded XPO1 from this study followed by Topaz picking
CTF correctionSoftware - Name: cryoSPARC / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE / Details: Ab initio
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.37 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 431664
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
FSC plot (resolution estimation)

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Atomic model buiding 1

Initial modelChain - Source name: Other / Chain - Initial model type: experimental model / Details: unliganded XPO1 from this study
DetailsInitial model was docked into maps using UCSF ChimeraX then manually built using Isolde and Coot and refined in PHENIX
RefinementSpace: REAL / Protocol: OTHER / Overall B value: 148.94
Output model

PDB-9oga:
Cryo-EM structure of human full-length XPO1 conjugated with selinexor

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