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 | |
| State | Published - Jan 22 2013 |
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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 journal › Article
}
TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=84872854571&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84872854571&partnerID=8YFLogxK
U2 - 10.1073/pnas.1217203110
DO - 10.1073/pnas.1217203110
M3 - Article
C2 - 23297231
AN - SCOPUS:84872854571
VL - 110
SP - 1303
EP - 1308
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 4
ER -