8VGZ

Influenza PA-N Endonuclease E23K Mutant (amino acids 52-74 truncation)

8VGZ の概要

• エントリーDOI: 10.2210/pdb8vgz/pdb
• 関連するPDBエントリー: 8T5Z
• 分子名称: Protein PA-X, MANGANESE (II) ION (3 entities in total)
• 機能のキーワード: influenza endonuclease, resistance, drug discovery, metal-binding pharmacophore, hydrolase
• 由来する生物種: Influenza A virus (A/California/04/2009(H1N1))
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 20871.62

構造登録者

Kohlbrand, A.J.,Cohen, S.M. (登録日: 2023-12-30, 公開日: 2024-02-14)

主引用文献

Kohlbrand, A.J.,Stokes, R.W.,Sankaran, B.,Cohen, S.M.
Structural Studies of Inhibitors with Clinically Relevant Influenza Endonuclease Variants.
Biochemistry, 63:264-272, 2024

PubMed Abstract: Vital to the treatment of influenza is the use of antivirals such as Oseltamivir (Tamiflu) and Zanamivir (Relenza); however, antiviral resistance is becoming an increasing problem for these therapeutics. The RNA-dependent RNA polymerase acidic N-terminal (PA) endonuclease, a critical component of influenza viral replication machinery, is an antiviral target that was recently validated with the approval of Baloxavir Marboxil (BXM). Despite its clinical success, BXM has demonstrated susceptibility to resistance mutations, specifically the I38T, E23K, and A36 V mutants of PA. To better understand the effects of these mutations on BXM resistance and improve the design of more robust therapeutics, this study examines key differences in protein-inhibitor interactions with two inhibitors and the I38T, E23K, and A36 V mutants. Differences in inhibitor binding were evaluated by measuring changes in binding to PA using two biophysical methods. The binding mode of two distinct inhibitors was determined crystallographically with both wild-type and mutant forms of PA. Collectively, these studies give some insight into the mechanism of antiviral resistance of these mutants.

PubMed: 38190441
DOI: 10.1021/acs.biochem.3c00536

実験手法

X-RAY DIFFRACTION (2.09 Å)