5W2W

INFLUENZA VIRUS NEURAMINIDASE N9 IN COMPLEX WITH 8-DEOXYGENATED 2,3-DIFLUORO-N-ACETYLNEURAMINIC ACID

5W2W の概要

• エントリーDOI: 10.2210/pdb5w2w/pdb
• 関連するPDBエントリー: 5W26 5W2U 5W2Y
• 分子名称: Neuraminidase, alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-2)-alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-3)-[alpha-D-mannopyranose-(1-6)]alpha-D-mannopyranose-(1-6)]beta-D-mannopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• 機能のキーワード: influenza virus neuraminidase, n9, complex, 2, 3-difluorosialic acid, second binding site, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Influenza A virus (strain A/Tern/Australia/G70C/1975 H11N9)
• 細胞内の位置: Virion membrane : P03472
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 46871.61

構造登録者

Streltsov, V.A.,Mckimm-Breschkin, J.,Barrett, S.,Pilling, P.,Hader, S.,Watt, A.G. (登録日: 2017-06-07, 公開日: 2018-02-21, 最終更新日: 2024-10-30)

主引用文献

McKimm-Breschkin, J.L.,Barrett, S.,Pilling, P.A.,Hader, S.,Watts, A.G.,Streltsov, V.A.
Structural and Functional Analysis of Anti-Influenza Activity of 4-, 7-, 8- and 9-Deoxygenated 2,3-Difluoro- N-acetylneuraminic Acid Derivatives.
J. Med. Chem., 61:1921-1933, 2018

PubMed Abstract: Competitive inhibitors of the influenza neuraminidase (NA) were discovered almost 20 years ago, with zanamivir and oseltamivir licensed globally. These compounds are based on a transition state analogue of the sialic acid substrate. We recently showed that 5- N-(acetylamino)-2,3,5-trideoxy-2,3-difluoro-d-erythro-β-l-manno-2-nonulopyranosonic acid (DFSA) and its derivatives are also potent inhibitors of the influenza NA. They are mechanism based inhibitors, forming a covalent bond between the C2 of the sugar ring and Y406 in the NA active site, thus inactivating the enzyme. We have now synthesized a series of deoxygenated DFSA derivatives in order to understand the contribution of each hydroxyl in DFSA to binding and inhibition of the influenza NA. We have investigated their relative efficacy in enzyme assays in vitro, in cell culture, and by X-ray crystallography. We found loss of the 8- and 9-OH had the biggest impact on the affinity of binding and antiviral potency.

PubMed: 29397718
DOI: 10.1021/acs.jmedchem.7b01467

実験手法

X-RAY DIFFRACTION (1.85 Å)