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

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

Research output: Contribution to journalArticle

82 Citations (Scopus)

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 cargos for transport through the nuclear pore complex.

Original languageEnglish (US)
Pages (from-to)1303-1308
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume110
Issue number4
DOIs
StatePublished - Jan 22 2013

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Cell Nucleus Active Transport
Hydrolysis
Maintenance
Biological Products
Nuclear Export Signals
Karyopherins
Polyketides
Nuclear Pore
Lactones
Protein Transport
Mutagenesis
Carrier Proteins
leptomycin B
Proteins

ASJC Scopus subject areas

  • General

Cite this

Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. / Sun, Qingxiang; Carrasco, Yazmin P.; Hu, Youcai; Guo, Xiaofeng; Mirzaei, Hamid; MacMillan, John; Chook, Yuh Min.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 110, No. 4, 22.01.2013, p. 1303-1308.

Research output: Contribution to journalArticle

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