Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. Academic Article uri icon

Overview

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.

publication date

  • January 7, 2013

Research

keywords

  • Active Transport, Cell Nucleus
  • Karyopherins
  • Receptors, Cytoplasmic and Nuclear

Identity

PubMed Central ID

  • PMC3557022

Scopus Document Identifier

  • 84872854571

Digital Object Identifier (DOI)

  • 10.1073/pnas.1217203110

PubMed ID

  • 23297231

Additional Document Info

volume

  • 110

issue

  • 4