PDBsum entry 4hax

Protein transport/antibiotic

PDB id: 4hax

Contents

Protein chains

1017 a.a.

200 a.a.

131 a.a.

Ligands

RJA

GOL ×3

EDO ×3

GNP

Metals

_CL ×3

_MG

Waters ×1044

PDB id:

4hax

Name:

Protein transport/antibiotic

Title:

Crystal structure of crm1 inhibitor ratjadone a in complex with crm1(k579a)-ran-ranbp1

Structure:

Exportin-1. Chain: c. Fragment: see remark 999. Synonym: crm1, chromosome region maintenance protein 1, karyopherin- 124. Engineered: yes. Mutation: yes. Gtp-binding nuclear protein ran. Chain: a.

Source:

Saccharomyces cerevisiae. Yeast. Organism_taxid: 4932. Gene: crm1, kap124, xpo1, ygr218w, g8514. Expressed in: escherichia coli. Expression_system_taxid: 562. Homo sapiens. Human. Organism_taxid: 9606.

Resolution:

2.28Å R-factor: 0.174 R-free: 0.216

Authors:

Q.Sun,Y.M.Chook

Key ref:

Q.Sun et al. (2013). Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1. Proc Natl Acad Sci U S A, 110, 1303-1308. PubMed id: 23297231

Date:

27-Sep-12 Release date: 09-Jan-13

Protein chain

P30822  (XPO1_YEAST) -  Exportin-1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 1084 a.a.

Struc: 1017 a.a.*

Protein chain

P62826  (RAN_HUMAN) -  GTP-binding nuclear protein Ran from Homo sapiens

Seq: 216 a.a.

Struc: 200 a.a.

Protein chain

P41920  (YRB1_YEAST) -  Ran-specific GTPase-activating protein 1 from Saccharomyces cerevisiae (strain ATCC 204508 / S288c)

Seq: 201 a.a.

Struc: 131 a.a.*

* PDB and UniProt seqs differ at 4 residue positions (black crosses)

Enzyme reactions

• Enzyme class: Chain A: E.C.3.6.5.- - ?????

Proc Natl Acad Sci U S A 110:1303-1308 (2013)

PubMed id: 23297231

Nuclear export inhibition through covalent conjugation and hydrolysis of Leptomycin B by CRM1.

Q.Sun, Y.P.Carrasco, Y.Hu, X.Guo, H.Mirzaei, J.Macmillan, Y.M.Chook.

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 cargos for transport through the nuclear pore complex.