3NL0

Mutant P44S M296I of Foot-and-mouth disease Virus RNA-dependent RNA polymerase

3NL0 の概要

• エントリーDOI: 10.2210/pdb3nl0/pdb
• 関連するPDBエントリー: 1u09 1WNE 2E9R 2E9T 2E9Z 2EC0 3NKY
• 分子名称: 3D polymerase, 5'-R(P*UP*GP*GP*GP*CP*CP*C)-3', 5'-R(*G*GP*GP*CP*CP*C)-3', ... (5 entities in total)
• 機能のキーワード: foot-and-mouth disease virus picornavirus, 3d polymerase, rna dependent rna polymerase, transferase-rna complex, transferase/rna
• 由来する生物種: Foot-and-mouth disease virus - type C; 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 57429.61

構造登録者

Agudo, R.,Ferrer-Orta, C.,Arias, A.,Perez-Luque, R.,Verdaguer, N.,Domingo, E. (登録日: 2010-06-21, 公開日: 2011-07-13, 最終更新日: 2023-11-01)

主引用文献

Agudo, R.,Ferrer-Orta, C.,Arias, A.,de la Higuera, I.,Perales, C.,Perez-Luque, R.,Verdaguer, N.,Domingo, E.
A multi-step process of viral adaptation to a mutagenic nucleoside analogue by modulation of transition types leads to extinction-escape.
Plos Pathog., 6:e1001072-e1001072, 2010

PubMed Abstract: Resistance of viruses to mutagenic agents is an important problem for the development of lethal mutagenesis as an antiviral strategy. Previous studies with RNA viruses have documented that resistance to the mutagenic nucleoside analogue ribavirin (1-β-D-ribofuranosyl-1-H-1,2,4-triazole-3-carboxamide) is mediated by amino acid substitutions in the viral polymerase that either increase the general template copying fidelity of the enzyme or decrease the incorporation of ribavirin into RNA. Here we describe experiments that show that replication of the important picornavirus pathogen foot-and-mouth disease virus (FMDV) in the presence of increasing concentrations of ribavirin results in the sequential incorporation of three amino acid substitutions (M296I, P44S and P169S) in the viral polymerase (3D). The main biological effect of these substitutions is to attenuate the consequences of the mutagenic activity of ribavirin -by avoiding the biased repertoire of transition mutations produced by this purine analogue-and to maintain the replicative fitness of the virus which is able to escape extinction by ribavirin. This is achieved through alteration of the pairing behavior of ribavirin-triphosphate (RTP), as evidenced by in vitro polymerization assays with purified mutant 3Ds. Comparison of the three-dimensional structure of wild type and mutant polymerases suggests that the amino acid substitutions alter the position of the template RNA in the entry channel of the enzyme, thereby affecting nucleotide recognition. The results provide evidence of a new mechanism of resistance to a mutagenic nucleoside analogue which allows the virus to maintain a balance among mutation types introduced into progeny genomes during replication under strong mutagenic pressure.

PubMed: 20865120
DOI: 10.1371/journal.ppat.1001072

実験手法

X-RAY DIFFRACTION (2.6 Å)