6CF5

Crystal structure of the A/Viet Nam/1203/2004(H5N1) influenza virus hemagglutinin in complex with small molecule N-Cyclohexyltaurine

6CF5 の概要

• エントリーDOI: 10.2210/pdb6cf5/pdb
• 分子名称: Hemagglutinin, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, 2-[N-CYCLOHEXYLAMINO]ETHANE SULFONIC ACID, ... (8 entities in total)
• 機能のキーワード: glycoprotein, ectodomain, n-glycosylation, viral protein
• 由来する生物種: Influenza A virus (A/Viet Nam/1203/2004(H5N1)); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 178969.72

構造登録者

Wilson, I.A.,Kadam, R.U. (登録日: 2018-02-13, 公開日: 2018-04-04, 最終更新日: 2024-11-20)

主引用文献

Kadam, R.U.,Wilson, I.A.
A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin.
Proc. Natl. Acad. Sci. U.S.A., 115:4240-4245, 2018

PubMed Abstract: The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule -cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X-ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-Å and 2.57-Å resolution, respectively, revealed that -cyclohexyltaurine binds to the heart of the conserved HA RBS. -cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-π interactions with the HA. In H3/HK68, -cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. These long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance our knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus.

PubMed: 29610325
DOI: 10.1073/pnas.1801999115

実験手法

X-RAY DIFFRACTION (2.04 Å)