4GMX

Crystal structure of KPT185 in complex with CRM1-Ran-RanBP1

Summary for 4GMX

• Entry DOI: 10.2210/pdb4gmx/pdb
• Related: 4GPT
• Descriptor: GTP-binding nuclear protein Ran, Ran-specific GTPase-activating protein 1, Exportin-1, ... (10 entities in total)
• Functional Keywords: heat repeat, protein export, crm1, kpt185, nuclear, protein transport-inhibitor complex, protein transport/inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: P62826 P30822; Cytoplasm: P41920
• Total number of polymer chains: 3
• Total formula weight: 163913.20

Authors

Sun, Q.,Chook, Y.M. (deposition date: 2012-08-16, release date: 2012-10-17, Last modification date: 2024-10-16)

Primary citation

Lapalombella, R.,Sun, Q.,Williams, K.,Tangeman, L.,Jha, S.,Zhong, Y.,Goettl, V.,Mahoney, E.,Berglund, C.,Gupta, S.,Farmer, A.,Mani, R.,Johnson, A.J.,Lucas, D.,Mo, X.,Daelemans, D.,Sandanayaka, V.,Shechter, S.,McCauley, D.,Shacham, S.,Kauffman, M.,Chook, Y.M.,Byrd, J.C.
Selective inhibitors of nuclear export show that CRM1/XPO1 is a target in chronic lymphocytic leukemia.
Blood, 120:4621-4634, 2012

PubMed Abstract: The nuclear export protein XPO1 is overexpressed in cancer, leading to the cytoplasmic mislocalization of multiple tumor suppressor proteins. Existing XPO1-targeting agents lack selectivity and have been associated with significant toxicity. Small molecule selective inhibitors of nuclear export (SINEs) were designed that specifically inhibit XPO1. Genetic experiments and X-ray structures demonstrate that SINE covalently bind to a cysteine residue in the cargo-binding groove of XPO1, thereby inhibiting nuclear export of cargo proteins. The clinical relevance of SINEs was explored in chronic lymphocytic leukemia (CLL), a disease associated with recurrent XPO1 mutations. Evidence is presented that SINEs can restore normal regulation to the majority of the dysregulated pathways in CLL both in vitro and in vivo and induce apoptosis of CLL cells with a favorable therapeutic index, with enhanced killing of genomically high-risk CLL cells that are typically unresponsive to traditional therapies. More importantly, SINE slows disease progression, and improves overall survival in the Eμ-TCL1-SCID mouse model of CLL with minimal weight loss or other toxicities. Together, these findings demonstrate that XPO1 is a valid target in CLL with minimal effects on normal cells and provide a basis for the development of SINEs in CLL and related hematologic malignancies.

PubMed: 23034282
DOI: 10.1182/blood-2012-05-429506

Experimental method

X-RAY DIFFRACTION (2.1 Å)