4HAU: Crystal Structure of Crm1 Inhibitor Ratjadone a in Complex With Crm1- Ran-ranbp1

Citation:
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-A-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.
PDB ID: 4HAUDownload
MMDB ID: 106537
PDB Deposition Date: 2012/9/27
Updated in MMDB: 2017/07 
Experimental Method:
x-ray diffraction
Resolution: 2  Å
Source Organism:
Homo sapiens
Similar Structures:
Biological Unit for 4HAU: trimeric; determined by author and by software (PISA)
Molecular Components in 4HAU
Label Count Molecule
Proteins (3 molecules)
1
Gtp-binding Nuclear Protein RAN(Gene symbol: RAN)
Molecule annotation
1
Ran-specific Gtpase-activating Protein 1(Gene symbol: YRB1)
Molecule annotation
1
Exportin-1(Gene symbol: CRM1)
Molecule annotation
Chemicals (13 molecules)
1
1
2
1
3
4
4
1
5
3
6
3
* Click molecule labels to explore molecular sequence information.

Citing MMDB
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