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Literature DB >> 23297231

Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.

Qingxiang Sun¹, Yazmin P Carrasco, Youcai Hu, Xiaofeng Guo, Hamid Mirzaei, John Macmillan, Yuh Min Chook.

Abstract

The polyketide natural product Leptomycin B inhibits nuclear export mediated by the karyopherin protein chromosomal region maintenance 1 (CRM1). Here, we present 1.8- to 2.0-Å-resolution crystal structures of CRM1 bound to Leptomycin B and related inhibitors Anguinomycin A and Ratjadone A. Structural and complementary chemical analyses reveal an unexpected mechanism of inhibition involving covalent conjugation and CRM1-mediated hydrolysis of the natural products' lactone rings. Furthermore, mutagenesis reveals the mechanism of hydrolysis by CRM1. The nuclear export signal (NES)-binding groove of CRM1 is able to drive a chemical reaction in addition to binding protein cargoes for transport through the nuclear pore complex.

Entities: Chemical Gene

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Year: 2013 PMID： 23297231 PMCID： PMC3557022 DOI： 10.1073/pnas.1217203110

Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205

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