2KTZ

Inhibitor Induced Structural Change in the HCV IRES Domain IIa RNA

2KTZ の概要

• エントリーDOI: 10.2210/pdb2ktz/pdb
• 関連するPDBエントリー: 2KU0
• 分子名称: HCV IRES Domain IIa RNA, (7R)-7-[(dimethylamino)methyl]-1-[3-(dimethylamino)propyl]-7,8-dihydro-1H-furo[3,2-e]benzimidazol-2-amine (2 entities in total)
• 機能のキーワード: hepatitis c virus, rna structure, antiviral, rna
• 由来する生物種: Hepatitis C virus (HCV)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 12439.60

構造登録者

Paulsen, R.B.,Seth, P.P.,Swayze, E.E.,Griffey, R.H.,Skalicky, J.J.,Cheatham III, T.E.,Davis, D.R. (登録日: 2010-02-10, 公開日: 2010-04-28, 最終更新日: 2024-05-22)

主引用文献

Paulsen, R.B.,Seth, P.P.,Swayze, E.E.,Griffey, R.H.,Skalicky, J.J.,Cheatham, T.E.,Davis, D.R.
Inhibitor-induced structural change in the HCV IRES domain IIa RNA.
Proc.Natl.Acad.Sci.USA, 107:7263-7268, 2010

PubMed Abstract: Translation of the hepatitis C virus (HCV) RNA is initiated from a highly structured internal ribosomal entry site (IRES) in the 5' untranslated region (5' UTR) of the RNA genome. An important structural feature of the native RNA is an approximately 90 degrees helical bend localized to domain IIa that positions the apical loop of domain IIb of the IRES near the 40S ribosomal E-site to promote eIF2-GDP release, facilitating 80S ribosome assembly. We report here the NMR structure of a domain IIa construct in complex with a potent small-molecule inhibitor of HCV replication. Molecular dynamics refinement in explicit solvent and subsequent energetic analysis indicated that each inhibitor stereoisomer bound with comparable affinity and in an equivalent binding mode. The in silico analysis was substantiated by fluorescence-based assays showing that the relative binding free energies differed by only 0.7 kcal/mol. Binding of the inhibitor displaces key nucleotide residues within the bulge region, effecting a major conformational change that eliminates the bent RNA helical trajectory, providing a mechanism for the antiviral activity of this inhibitor class.

PubMed: 20360559
DOI: 10.1073/pnas.0911896107

実験手法

SOLUTION NMR