5WDC

Crystal structure of the influenza virus PA endonuclease in complex with inhibitor 9e (SRI-29843)

5WDC の概要

• エントリーDOI: 10.2210/pdb5wdc/pdb
• 関連するPDBエントリー: 5W3I 5W44 5W73 5W7U 5W92 5W9G 5WA6 5WA7 5WAP 5WB3 5WCS 5WCT
• 分子名称: Polymerase acidic protein, MANGANESE (II) ION, SULFATE ION, ... (5 entities in total)
• 機能のキーワード: virus, nuclease, transcription, cap-snatching, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Influenza A virus; 詳細
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23947.29

構造登録者

Kumar, G.,White, S.W. (登録日: 2017-07-04, 公開日: 2018-01-03, 最終更新日: 2024-03-13)

主引用文献

Beylkin, D.,Kumar, G.,Zhou, W.,Park, J.,Jeevan, T.,Lagisetti, C.,Harfoot, R.,Webby, R.J.,White, S.W.,Webb, T.R.
Protein-Structure Assisted Optimization of 4,5-Dihydroxypyrimidine-6-Carboxamide Inhibitors of Influenza Virus Endonuclease.
Sci Rep, 7:17139-17139, 2017

PubMed Abstract: Influenza is a serious hazard to human health that causes hundreds of thousands of deaths annually. Though vaccines and current therapeutics can blunt some of the perilous impact of this viral infection, new treatments are needed due to the constantly evolving nature of this virus. Recently, our growing understanding of an essential influenza viral protein, PA, has led to the development of focused libraries of new small molecules that specifically target the active site of the PA influenza endonuclease, which we report here. Our overarching approach has been to proactively develop lead inhibitors that are less likely to rapidly develop clinical resistance by optimizing inhibitors that retain activity against induced resistant mutants. Here, we report details behind the discovery of new potent inhibitors of wild type and resistant mutant endonucleases along with their high-resolution co-crystal structure-activity relationships. These results add to our understanding of nuclease protein targets and potentially serve as starting points for a new therapeutic approach to the treatment of influenza.

PubMed: 29215062
DOI: 10.1038/s41598-017-17419-6

実験手法

X-RAY DIFFRACTION (2.1 Å)