PDBsum entry: 1mn9

Transferase

PDB id: 1mn9

Contents

Protein chains

150 a.a. *

Ligands

RTP ×3

Metals

_MG ×3

Waters ×38

* Residue conservation analysis

PDB id:

1mn9

Name:

Transferase

Title:

Ndp kinase mutant (h122g) complex with rtp

Structure:

Ndp kinase. Chain: a, b, c. Synonym: nucleoside diphosphate kinase, cytosolic. Engineered: yes. Mutation: yes

Source:

Dictyostelium discoideum. Organism_taxid: 44689. Expressed in: escherichia coli. Expression_system_taxid: 562

Biol. unit:

Hexamer (from PDB file)

Resolution:

2.90Å R-factor: 0.207 R-free: 0.249

Authors:

S.Gallois-Montbrun,Y.Chen,H.Dutartre,S.Morera,C.Guerreiro,L. B.Schneider,J.Janin,B.Canard,M.Veron,D.Deville-Bonne

Key ref:

S.Gallois-Montbrun et al. (2003). Structural analysis of the activation of ribavirin analogs by NDP kinase: comparison with other ribavirin targets. Mol Pharmacol, 63, 538-546. PubMed id: 12606760 DOI: 10.1124/mol.63.3.538

Date:

05-Sep-02 Release date: 18-Mar-03

Protein chains

P22887  (NDKC_DICDI) -  Nucleoside diphosphate kinase, cytosolic

Seq: 155 a.a.

Struc: 150 a.a.*

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: E.C.2.7.4.6 - Nucleoside-diphosphate kinase.
• Reaction: ATP + nucleoside diphosphate = ADP + nucleoside triphosphate

ATP (Bound ligand (Het Group name = RTP) matches with 81.82% similarity) + nucleoside diphosphate = ADP + nucleoside triphosphate

Molecule diagrams generated from .mol files obtained from the KEGG ftp site

 Gene Ontology (GO) functional annotation 

• Cellular component: plasma membrane (6 terms)
• Biological process: cytoskeleton organization (13 terms)
• Biochemical function: nucleotide binding (6 terms)

reference

DOI no: 10.1124/mol.63.3.538

Mol Pharmacol 63:538-546 (2003)

PubMed id: 12606760

Structural analysis of the activation of ribavirin analogs by NDP kinase: comparison with other ribavirin targets.

S.Gallois-Montbrun, Y.Chen, H.Dutartre, M.Sophys, S.Morera, C.Guerreiro, B.Schneider, L.Mulard, J.Janin, M.Veron, D.Deville-Bonne, B.Canard.

ABSTRACT

Ribavirin used in therapies against hepatitis C virus (HCV) is potentially efficient against other viruses but presents a high cytotoxicity. Several ribavirin triphosphate analogs modified on the ribose moiety were synthesized and tested in vitro on the RNA polymerases of HCV, phage T7, and HIV-1 reverse transcriptase. Modified nucleotides with 2'-deoxy, 3'-deoxy, 2',3'-dideoxy, 2',3'-dideoxy-2',3'-dehydro, and 2',3'-epoxy-ribose inhibited the HCV enzyme but not the other two polymerases. They were also analyzed as substrates for nucleoside diphosphate (NDP) kinase, the enzyme responsible for the last step of the cellular activation of antiviral nucleoside analogs. An X-ray structure of NDP kinase complexed with ribavirin triphosphate was determined. It demonstrates that the analog binds as a normal substrate despite the modified base and confirms the crucial role of the 3'-hydroxyl group in the phosphorylation reaction. The 3'-hydroxyl is required for inhibition of the initiation step of RNA synthesis by HCV polymerase, and both sugar hydroxyls must be present to inhibit elongation. The 2'deoxyribavirin is the only derivative efficient in vitro against HCV polymerase and properly activated by NDP kinase.