Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.
basic_science · Level V
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- Record sourced from PubMed, PMID 23297231.
- Also identified by DOI 10.1073/pnas.1217203110 and PMC identifier 3557022.
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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 cargoes for transport through the nuclear pore complex.
Medical subject headings
- Active Transport, Cell Nucleus
- Karyopherins
- Receptors, Cytoplasmic and Nuclear