1MN9

NDP kinase mutant (H122G) complex with RTP

Summary for 1MN9

• Entry DOI: 10.2210/pdb1mn9/pdb
• Related: 1f3f 1nue
• Descriptor: NDP kinase, MAGNESIUM ION, RIBAVIRIN TRIPHOSPHATE, ... (4 entities in total)
• Functional Keywords: ndp kinase-ribavirin complex, transferase
• Biological source: Dictyostelium discoideum
• Cellular location: Cytoplasm: P22887
• Total number of polymer chains: 3
• Total formula weight: 51731.07

Authors

Gallois-montbrun, S.,Chen, Y.,Dutartre, H.,Morera, S.,Guerreiro, C.,Mulard, L.,Schneider, B.,Janin, J.,Canard, B.,Veron, M.,Deville-bonne, D. (deposition date: 2002-09-05, release date: 2003-03-18, Last modification date: 2024-05-29)

Primary citation

Gallois-montbrun, S.,Chen, Y.,Dutartre, H.,Sophys, M.,Morera, S.,Guerreiro, C.,Schneider, B.,Mulard, L.,Janin, J.,Veron, M.,Deville-bonne, D.,Canard, B.
Structural Analysis of the Activation of Ribavirin Analogs by NDP Kinase: Comparison with Other Ribavirin Targets
MOL.PHARMACOL., 63:538-546, 2003

PubMed 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.

PubMed: 12606760
DOI: 10.1124/mol.63.3.538

Experimental method

X-RAY DIFFRACTION (2.9 Å)