- Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.
Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.
Proceedings of the National Academy of Sciences of the United States of America (2013-01-09)
Qingxiang Sun, Yazmin P Carrasco, Youcai Hu, Xiaofeng Guo, Hamid Mirzaei, John Macmillan, Yuh Min Chook
PMID23297231
摘要
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.