4HB4

Crystal structure of CRM1 inhibitor Leptomycin B in complex with CRM1(537DLTVK541/GLCEQ)-Ran-RanBP1

Summary for 4HB4

• Entry DOI: 10.2210/pdb4hb4/pdb
• Related: 4GMX 4GPT 4HAT 4HAU 4HAV 4HAW 4HAX 4HAY 4HAZ 4HB0 4HB2 4HB3
• Descriptor: GTP-binding nuclear protein Ran, Ran-specific GTPase-activating protein 1, Exportin-1, ... (10 entities in total)
• Functional Keywords: heat repeat, nuclear export, ran-ranbp1, lmb, leptomycin b, protein transport-antibiotic complex, protein transport/antibiotic
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus : P62826 P30822; Cytoplasm: P41920
• Total number of polymer chains: 3
• Total formula weight: 159669.96

Authors

Sun, Q.,Chook, Y.M. (deposition date: 2012-09-27, release date: 2013-01-09, Last modification date: 2024-11-06)

Primary citation

Sun, Q.,Carrasco, Y.P.,Hu, Y.,Guo, X.,Mirzaei, H.,Macmillan, J.,Chook, Y.M.
Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.
Proc.Natl.Acad.Sci.USA, 110:1303-1308, 2013

PubMed 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.

PubMed: 23297231
DOI: 10.1073/pnas.1217203110

Experimental method

X-RAY DIFFRACTION (2.05 Å)