5CGV

2009 H1N1 PA endonuclease in complex with L-742,001

5CGV の概要

• エントリーDOI: 10.2210/pdb5cgv/pdb
• 分子名称: Polymerase acidic protein, MANGANESE (II) ION, (2Z)-4-[1-benzyl-4-(4-chlorobenzyl)piperidin-4-yl]-2-hydroxy-4-oxobut-2-enoic acid, ... (5 entities in total)
• 機能のキーワード: influenza resistance endonuclease inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Influenza A virus
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 22586.02

構造登録者

Kumar, G.,White, S.W. (登録日: 2015-07-09, 公開日: 2016-03-23, 最終更新日: 2023-09-27)

主引用文献

Song, M.S.,Kumar, G.,Shadrick, W.R.,Zhou, W.,Jeevan, T.,Li, Z.,Slavish, P.J.,Fabrizio, T.P.,Yoon, S.W.,Webb, T.R.,Webby, R.J.,White, S.W.
Identification and characterization of influenza variants resistant to a viral endonuclease inhibitor.
Proc. Natl. Acad. Sci. U.S.A., 113:3669-3674, 2016

PubMed Abstract: The influenza endonuclease is an essential subdomain of the viral RNA polymerase. It processes host pre-mRNAs to serve as primers for viral mRNA and is an attractive target for antiinfluenza drug discovery. Compound L-742,001 is a prototypical endonuclease inhibitor, and we found that repeated passaging of influenza virus in the presence of this drug did not lead to the development of resistant mutant strains. Reduced sensitivity to L-742,001 could only be induced by creating point mutations via a random mutagenesis strategy. These mutations mapped to the endonuclease active site where they can directly impact inhibitor binding. Engineered viruses containing the mutations showed resistance to L-742,001 both in vitro and in vivo, with only a modest reduction in fitness. Introduction of the mutations into a second virus also increased its resistance to the inhibitor. Using the isolated wild-type and mutant endonuclease domains, we used kinetics, inhibitor binding and crystallography to characterize how the two most significant mutations elicit resistance to L-742,001. These studies lay the foundation for the development of a new class of influenza therapeutics with reduced potential for the development of clinical endonuclease inhibitor-resistant influenza strains.

PubMed: 26976575
DOI: 10.1073/pnas.1519772113

実験手法

X-RAY DIFFRACTION (2.17 Å)