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Cells 2015, 4(3), 538-568; doi:10.3390/cells4030538

Structural Basis of Targeting the Exportin CRM1 in Cancer

Abteilung für Molekulare Strukturbiologie, Institut für Mikrobiologie und Genetik, GZMB, Georg-August-Universität Göttingen, Justus-von-Liebig-Weg 11, Göttingen 37077, Germany
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Academic Editor: Birthe Fahrenkrog
Received: 2 July 2015 / Revised: 7 September 2015 / Accepted: 11 September 2015 / Published: 21 September 2015
(This article belongs to the Special Issue Nucleocytoplasmic Transport)
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Abstract

Recent studies have demonstrated the interference of nucleocytoplasmic trafficking with the establishment and maintenance of various cancers. Nucleocytoplasmic transport is highly regulated and coordinated, involving different nuclear transport factors or receptors, importins and exportins, that mediate cargo transport from the cytoplasm into the nucleus or the other way round, respectively. The exportin CRM1 (Chromosome region maintenance 1) exports a plethora of different protein cargoes and ribonucleoprotein complexes. Structural and biochemical analyses have enabled the deduction of individual steps of the CRM1 transport cycle. In addition, CRM1 turned out to be a valid target for anticancer drugs as it exports numerous proto-oncoproteins and tumor suppressors. Clearly, detailed understanding of the flexibility, regulatory features and cooperative binding properties of CRM1 for Ran and cargo is a prerequisite for the design of highly effective drugs. The first compound found to inhibit CRM1-dependent nuclear export was the natural drug Leptomycin B (LMB), which blocks export by competitively interacting with a highly conserved cleft on CRM1 required for nuclear export signal recognition. Clinical studies revealed serious side effects of LMB, leading to a search for alternative natural and synthetic drugs and hence a multitude of novel therapeutics. The present review examines recent progress in understanding the binding mode of natural and synthetic compounds and their inhibitory effects. View Full-Text
Keywords: XPO1; exportin1; nuclear transport; NES; cancer; CRM1; drugs; inhibitor XPO1; exportin1; nuclear transport; NES; cancer; CRM1; drugs; inhibitor
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Dickmanns, A.; Monecke, T.; Ficner, R. Structural Basis of Targeting the Exportin CRM1 in Cancer. Cells 2015, 4, 538-568.

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