1MN9

NDP kinase mutant (H122G) complex with RTP

1MN9 の概要

• エントリーDOI: 10.2210/pdb1mn9/pdb
• 関連するPDBエントリー: 1f3f 1nue
• 分子名称: NDP kinase, MAGNESIUM ION, RIBAVIRIN TRIPHOSPHATE, ... (4 entities in total)
• 機能のキーワード: ndp kinase-ribavirin complex, transferase
• 由来する生物種: Dictyostelium discoideum
• 細胞内の位置: Cytoplasm: P22887
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 51731.07

構造登録者

Gallois-montbrun, S.,Chen, Y.,Dutartre, H.,Morera, S.,Guerreiro, C.,Mulard, L.,Schneider, B.,Janin, J.,Canard, B.,Veron, M.,Deville-bonne, D. (登録日: 2002-09-05, 公開日: 2003-03-18, 最終更新日: 2024-05-29)

主引用文献

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

実験手法

X-RAY DIFFRACTION (2.9 Å)