9OGO

Crystal Structure of KPT185 in complex with CRM1(EH mutant)-Ran-RanBP1

Summary for 9OGO

• Entry DOI: 10.2210/pdb9ogo/pdb
• Related: 9OGD
• Descriptor: GTP-binding nuclear protein Ran, Ran-specific GTPase-activating protein 1, Exportin-1, ... (9 entities in total)
• Functional Keywords: exportin, sine, export, xpo1, transport protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 161804.68

Authors

Fung, H.Y.J.,Chook, Y.M. (deposition date: 2025-05-01, release date: 2025-11-26, Last modification date: 2025-12-03)

Primary citation

Wing, C.E.,Fung, H.Y.J.,Kwanten, B.,Cagatay, T.,Niesman, A.B.,Jacquemyn, M.,Gharghabi, M.,Permentier, B.,Shakya, B.,Nandi, R.,Ready, J.M.,Kashyap, T.,Shacham, S.,Landesman, Y.,Lapalombella, R.,Daelemans, D.,Chook, Y.M.
SINE compounds activate exportin-1 degradation via an allosteric mechanism.
Biorxiv, 2025

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 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.

PubMed: 39416201
DOI: 10.1101/2024.10.07.617049

Experimental method

X-RAY DIFFRACTION (2.37 Å)