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- PDB-11rm: Cryo-EM structure of human exportin-1 conjugated with FR-027* -

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Basic information

Entry
Database: PDB / ID: 11rm
TitleCryo-EM structure of human exportin-1 conjugated with FR-027*
ComponentsExportin-1
KeywordsPROTEIN TRANSPORT / nuclear transport / inhibitor
Function / homology
Function and homology information


cellular response to triglyceride / cellular response to salt / HuR (ELAVL1) binds and stabilizes mRNA / annulate lamellae / nuclear export signal receptor activity / regulation of proteasomal ubiquitin-dependent protein catabolic process / Rev-mediated nuclear export of HIV RNA / NEP/NS2 Interacts with the Cellular Export Machinery / nucleocytoplasmic transport / Maturation of hRSV A proteins ...cellular response to triglyceride / cellular response to salt / HuR (ELAVL1) binds and stabilizes mRNA / annulate lamellae / nuclear export signal receptor activity / regulation of proteasomal ubiquitin-dependent protein catabolic process / Rev-mediated nuclear export of HIV RNA / NEP/NS2 Interacts with the Cellular Export Machinery / nucleocytoplasmic transport / Maturation of hRSV A proteins / ribosomal large subunit export from nucleus / Estrogen-dependent nuclear events downstream of ESR-membrane signaling / protein 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 / 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 / Maturation of DENV proteins / RHO GTPases Activate Formins / Deactivation of the beta-catenin transactivating complex / 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 / nucleoplasm / membrane / 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)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.95 Å
AuthorsWing, C.E. / Fung, H.Y.J. / Chook, Y.M.
Funding support United States, 5items
OrganizationGrant numberCountry
Cancer Prevention and Research Institute of Texas (CPRIT)RP220582 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R24GM154185 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM144137 United States
Cancer Prevention and Research Institute of Texas (CPRIT)RP210041 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)T32GM131963 United States
CitationJournal: Nat Commun / Year: 2026
Title: Preclinical characterization of a reversible XPO1 inhibitor for cancer therapy.
Authors: Janne Van Hauwenhuyse / Felien Reniers / Leentje Persoons / Sam Noppen / Casey E Wing / Ashley B Niesman / Ho Yee Joyce Fung / Els Vanstreels / Maarten Jacquemyn / Eline Boel / Ann ...Authors: Janne Van Hauwenhuyse / Felien Reniers / Leentje Persoons / Sam Noppen / Casey E Wing / Ashley B Niesman / Ho Yee Joyce Fung / Els Vanstreels / Maarten Jacquemyn / Eline Boel / Ann Vankerckhoven / Yani Berckmans / Bert Kwanten / An Coosemans / Guy Van den Mooter / Yuh Min Chook / Wim Dehaen / Dirk Daelemans /
Abstract: Exportin 1 (XPO1/CRM1) is a clinically validated anticancer target whose inhibition blocks nuclear export and promotes cancer cell apoptosis. Current XPO1 inhibitors rely on covalent Michael addition ...Exportin 1 (XPO1/CRM1) is a clinically validated anticancer target whose inhibition blocks nuclear export and promotes cancer cell apoptosis. Current XPO1 inhibitors rely on covalent Michael addition to Cys528 in the nuclear export signal binding groove of XPO1. Here, we describe a novel XPO1 inhibitor, FR-027, that targets Cys528 through nucleophilic aromatic substitution. In contrast to clinical-stage XPO1 inhibitors selinexor and eltanexor, FR-027 acts reversibly and does not promote XPO1 protein degradation. Structural analysis of the XPO1-FR-027 complex reveals covalent modification of Cys528 and a closed-groove conformation that prevents degradation. FR-027 demonstrates potent on-target activity across multiple cancer cell types and delays disease progression while extending overall survival in xenograft and syngeneic models, including intracranial tumors. Notably, FR-027 does not induce significant thrombocytopenia, lymphopenia, or neutropenia in heavily treated mice. These findings underscore the distinct molecular and pharmacological properties of FR-027 and support its further evaluation for clinical development in diseases with significant unmet medical needs.
History
DepositionMar 10, 2026Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2026Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jul 29, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release
Revision 1.1Sep 9, 2026Group: Data collection / Database references / Category: citation / em_admin
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update
Revision 1.1Sep 9, 2026Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Database references / Experimental summary / Data content type: EM metadata / EM metadata / Category: citation / em_admin
Data content type: EM metadata / EM metadata ...EM metadata / EM metadata / EM metadata / EM metadata
Item: _citation.journal_volume / _citation.pdbx_database_id_PubMed ..._citation.journal_volume / _citation.pdbx_database_id_PubMed / _citation.title / _em_admin.last_update

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Exportin-1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)123,7902
Polymers123,6621
Non-polymers1271
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, covalently bound to FR-027* at C528
Source: (gene. exp.) Homo sapiens (human) / Gene: XPO1, CRM1 / Plasmid: pGEX4TT3 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: O14980
#2: Chemical ChemComp-A1DBJ / 1-methyl-4-nitro-1H-imidazole


Mass: 127.101 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H5N3O2
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: Full-length human XPO1 conjugated to FR-027* / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.124 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, 150 mM NaCl, 2 mM Mg(OAc)2, 2 mM TCEP, 0.025% Tyloxapol
Buffer component
IDConc.NameFormulaBuffer-ID
120 mMHEPES1
2150 mMSodium chlorideNaCl1
32 mMMagnesium acetateMg(CH3COO)21
42 mMTCEP1
50.025 %Tyloxapol1
SpecimenConc.: 3 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: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 95 % / Chamber temperature: 280 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 / Cs: 2.7 mm
Specimen holderSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 25729
EM imaging opticsEnergyfilter name: TFS Selectris X / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
7UCSF ChimeraXmodel fitting
8ISOLDEmodel fitting
9Cootmodel fitting
11cryoSPARCinitial Euler assignment
12cryoSPARCfinal Euler assignment
13cryoSPARCclassification
14cryoSPARC3D reconstruction
15PHENIX1.19.1_4122model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 1867386 / Details: blob picking followed by Topaz picking
3D reconstructionResolution: 2.95 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 630291 / Symmetry type: POINT
Atomic model buildingB value: 179.36 / 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 buildingPDB-ID: 9OG9

9og9


Pdb chain-ID: A / Accession code: 9OG9 / Details: starting model for XPO1 / Source name: PDB / Type: experimental model
RefinementHighest resolution: 2.95 Å / Cross valid method: NONE
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027222
ELECTRON MICROSCOPYf_angle_d0.4419788
ELECTRON MICROSCOPYf_dihedral_angle_d3.394925
ELECTRON MICROSCOPYf_chiral_restr0.0341121
ELECTRON MICROSCOPYf_plane_restr0.0031253

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