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-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.
authors.affiliation: Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390-9041, USA.
authors.forename: Qingxiang
authors.initials: Q
authors.lastname: Sun
authors.forename: Yazmin P
authors.initials: YP
authors.lastname: Carrasco
authors.forename: Youcai
authors.initials: Y
authors.lastname: Hu
authors.forename: Xiaofeng
authors.initials: X
authors.lastname: Guo
authors.forename: Hamid
authors.initials: H
authors.lastname: Mirzaei
authors.forename: John
authors.initials: J
authors.lastname: Macmillan
authors.forename: Yuh Min
authors.initials: YM
authors.lastname: Chook
mesh_terms: D000179:Acrylates / Q000737:chemistry / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D019943:Amino Acid Substitution; D018360:Crystallography, X-Ray; D005231:Fatty Acids, Unsaturated / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006868:Hydrolysis; D028884:Karyopherins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D008953:Models, Anatomic; D016297:Mutagenesis, Site-Directed; D049790:Nuclear Export Signals / Q000235:genetics; D011487:Protein Conformation; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055672:Static Electricity; D014230:Triazoles / Q000737:chemistry / Q000494:pharmacology; D000097606:Exportin 1 Protein
chemical_list: D000179:Acrylates; D005231:Fatty Acids, Unsaturated; D028884:Karyopherins; D049790:Nuclear Export Signals; D018160:Receptors, Cytoplasmic and Nuclear; D029701:Saccharomyces cerevisiae Proteins; D014230:Triazoles; D000097606:Exportin 1 Protein; C576639:KPT-185; C038753:leptomycin B