Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	SINE compounds activate exportin 1 degradation through an allosteric mechanism.
Journal, issue, pages	Nat. Chem. Biol., Vol. 21, Page 2002-2013, Year 2025
Publish date	Apr 30, 2025
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 /
PubMed 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.
External links	Nat. Chem. Biol. / PubMed:41286136
Methods	EM (single particle) / X-ray diffraction
Resolution	2.37 - 4.21 Å
Structure data	70458 9og9 EMDB-70458, PDB-9og9: Cryo-EM structure of human full-length XPO1 (unliganded) Method: EM (single particle) / Resolution: 2.93 Å 70459 9oga EMDB-70459, PDB-9oga: Cryo-EM structure of human full-length XPO1 conjugated with selinexor Method: EM (single particle) / Resolution: 3.37 Å 70460 9ogb EMDB-70460, PDB-9ogb: Cryo-EM structure of human exportin-1 conjugated with selinexor and bound to yeast RAN-GTP and human ASB8-ELOB/C Method: EM (single particle) / Resolution: 3.25 Å 70461 9ogc EMDB-70461, PDB-9ogc: Cryo-EM structure of human exportin-1 conjugated with KPT-185 and bound to human ASB8-ELOB/C Method: EM (single particle) / Resolution: 3.37 Å 70462 9ogd EMDB-70462, PDB-9ogd: Cryo-EM structure of human exportin-1 conjugated with selinexor and bound to human ASB8(R197A)-ELOB/C Method: EM (single particle) / Resolution: 2.49 Å 70463 9oge EMDB-70463, PDB-9oge: Cryo-EM structure of human exportin-1 conjugated with KPT-127 and bound to human ASB8-ELOB/C Method: EM (single particle) / Resolution: 3.28 Å 70464 9ogf EMDB-70464, PDB-9ogf: Cryo-EM structure of human exportin-1 conjugated with KPT-UTSW1 and bound to human ASB8-ELOB/C Method: EM (single particle) / Resolution: 4.21 Å PDB-9ogn: Crystal Structure of KPT396 in complex with CRM1-Ran-RanBP1 Method: X-RAY DIFFRACTION / Resolution: 2.414 Å PDB-9ogo: Crystal Structure of KPT185 in complex with CRM1(EH mutant)-Ran-RanBP1 Method: X-RAY DIFFRACTION / Resolution: 2.37 Å
Chemicals	ChemComp-V6A: selinexor, bound form ChemComp-GTP: GUANOSINE-5'-TRIPHOSPHATE / GTP, energy-carrying moleculeYM ChemComp-MG: Unknown entry ChemComp-K85: propan-2-yl 3-{3-[3-methoxy-5-(trifluoromethyl)phenyl]-1H-1,2,4-triazol-1-yl}propanoate PDB-1cbc: Unknown entry PDB-1cbb: Unknown entry ChemComp-GNP: PHOSPHOAMINOPHOSPHONIC ACID-GUANYLATE ESTER / GppNHp, GMPPNP, energy-carrying molecule analogueYM ChemComp-GOL: GLYCEROL ChemComp-CL: Unknown entry PDB-1cbd: Unknown entry ChemComp-HOH: WATER
Source	homo sapiens (human) saccharomyces cerevisiae (brewer's yeast)
Keywords	PROTEIN TRANSPORT / nuclear export / HEAT repeat / inhibitor / protein degradation / TRANSPORT PROTEIN / Exportin / SINE / Export / XPO1