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 via an allosteric mechanism.
Journal, issue, pages	bioRxiv, Year 2025
Publish date	Jun 9, 2025
Authors	Casey Elizabeth 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	The nuclear export receptor exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells, leading to the mislocalization of numerous cancer-related protein cargoes . Selinexor, a covalent XPO1 ...The nuclear export receptor exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells, leading to the mislocalization of numerous cancer-related protein cargoes . Selinexor, a covalent XPO1 inhibitor, and other Selective Inhibitor of Nuclear Export (SINEs) restore proper nuclear localization by blocking XPO1-cargo binding . SINEs also induce XPO1 degradation via the Cullin-RING E3 ubiquitin ligase (CRL) substrate receptor ASB8 . Here we elucidate the mechanism underlying the high-affinity engagement of CRL5 with SINE-conjugated XPO1. Cryogenic electron microscopy (cryoEM) structures reveal that ASB8 binds to a cryptic site on XPO1, which becomes accessible only upon SINE conjugation. While molecular glue degraders typically interact with both CRL and the substrate , SINEs bind to XPO1 without requiring interaction with ASB8 for efficient XPO1 degradation. Instead, an allosteric mechanism facilitates high affinity XPO1-ASB8 interaction, leading to XPO1 ubiquitination and degradation. ASB8-mediated degradation is also observed upon treatment of the endogenous itaconate derivate 4-octyl itaconate, which suggests a native mechanism that is inadvertently exploited by synthesized XPO1 inhibitors. This allosteric XPO1 degradation mechanism of SINE compounds expands the known modes of targeted protein degradation beyond the well-characterized molecular glue degraders and proteolysis targeting chimeras of CRL4.
External links	bioRxiv / PubMed:39416201 / PubMed Central
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