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

doi:10.1073/pnas.1217203110

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

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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 language	English (US)
Pages (from-to)	1303-1308
Number of pages	6
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	110
Issue number	4
DOIs	https://doi.org/10.1073/pnas.1217203110
State	Published - Jan 22 2013

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title = "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-{\AA}-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.",

author = "Qingxiang Sun and Carrasco, {Yazmin P.} and Youcai Hu and Xiaofeng Guo and Hamid Mirzaei and John MacMillan and Chook, {Yuh Min}",

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T1 - Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1

AU - Sun, Qingxiang

AU - Carrasco, Yazmin P.

AU - Hu, Youcai

AU - Guo, Xiaofeng

AU - Mirzaei, Hamid

AU - MacMillan, John

AU - Chook, Yuh Min

PY - 2013/1/22

Y1 - 2013/1/22

N2 - 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.

AB - 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.

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

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