Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1
Copyright policy )Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1
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.
- The University of Texas Southwestern Medical Center United States
Models, Anatomic, Nuclear Export Signals, Saccharomyces cerevisiae Proteins, Protein Conformation, Hydrolysis, Static Electricity, Active Transport, Cell Nucleus, Receptors, Cytoplasmic and Nuclear, Exportin 1 Protein, Karyopherins, Triazoles, Crystallography, X-Ray, Acrylates, Amino Acid Substitution, Fatty Acids, Unsaturated, Mutagenesis, Site-Directed, Humans
Models, Anatomic, Nuclear Export Signals, Saccharomyces cerevisiae Proteins, Protein Conformation, Hydrolysis, Static Electricity, Active Transport, Cell Nucleus, Receptors, Cytoplasmic and Nuclear, Exportin 1 Protein, Karyopherins, Triazoles, Crystallography, X-Ray, Acrylates, Amino Acid Substitution, Fatty Acids, Unsaturated, Mutagenesis, Site-Directed, Humans
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