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


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.

SUBMITTER: Sun Q 

PROVIDER: S-EPMC3557022 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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

Sun Qingxiang Q   Carrasco Yazmin P YP   Hu Youcai Y   Guo Xiaofeng X   Mirzaei Hamid H   Macmillan John J   Chook Yuh Min YM  

Proceedings of the National Academy of Sciences of the United States of America 20130107 4


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, muta  ...[more]

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