Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1
| Autor: | Qingxiang Sun, Yuh Min Chook, Hamid Mirzaei, Yazmin P. Carrasco, John B. MacMillan, Youcai Hu, Xiaofeng Guo |
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| Rok vydání: | 2013 |
| Předmět: |
Models
Anatomic Saccharomyces cerevisiae Proteins Protein Conformation Stereochemistry Static Electricity Active Transport Cell Nucleus Receptors Cytoplasmic and Nuclear Karyopherins Crystallography X-Ray environment and public health XPO1 Protein structure Humans Nuclear pore Nuclear export signal Karyopherin Nuclear Export Signals chemistry.chemical_classification Multidisciplinary Hydrolysis Binding protein fungi Triazoles Biological Sciences Transport protein Acrylates Amino Acid Substitution chemistry Chromosomal region Fatty Acids Unsaturated Mutagenesis Site-Directed lipids (amino acids peptides and proteins) |
| Zdroj: | Proceedings of the National Academy of Sciences. 110:1303-1308 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1217203110 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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