6OJ7

Respiratory syncytial virus fusion glycoprotein N-terminal heptad repeat domain+VIQKI I456F

6OJ7 の概要

• エントリーDOI: 10.2210/pdb6oj7/pdb
• 分子名称: Fusion glycoprotein F0 (3 entities in total)
• 機能のキーワード: fusion protein, fusion inhibitor, six-helix bundle, antiviral protein
• 由来する生物種: Human respiratory syncytial virus A; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 9793.45

構造登録者

Outlaw, V.K.,Gellman, S.H. (登録日: 2019-04-10, 公開日: 2020-02-05, 最終更新日: 2024-10-16)

主引用文献

Outlaw, V.K.,Lemke, J.T.,Zhu, Y.,Gellman, S.H.,Porotto, M.,Moscona, A.
Structure-Guided Improvement of a Dual HPIV3/RSV Fusion Inhibitor.
J.Am.Chem.Soc., 142:2140-2144, 2020

PubMed Abstract: Human parainfluenza virus 3 (HPIV3) and respiratory syncytial virus (RSV) are leading causes of lower respiratory tract infections. There are currently no vaccines or antiviral therapeutics to treat HPIV3 or RSV infections. We recently reported a peptide (VIQKI), derived from the C-terminal heptad repeat (HRC) domain of the HPIV3 fusion (F) glycoprotein that inhibits infection by both HPIV3 and RSV. The dual inhibitory activity of VIQKI is due to its unique ability to bind to the N-terminal heptad repeat (HRN) domains of both HPIV3 and RSV F, thereby preventing the native HRN-HRC interactions required for viral entry. Here we describe the structure-guided design of dual inhibitors of HPIV3 and RSV fusion with improved efficacy. We show that VIQKI derivatives possessing one (I456F) or two (I454F/I456F) phenylalanine substitutions near the N-terminus exhibit more stable assemblies with the RSV-HRN domain and enhanced antiviral efficacy against both HPIV3 and RSV infection. Cocrystal structures of the new Phe-substituted inhibitors coassembled with HPIV3 or RSV-HRN domains reveal that the I456F substitution makes intimate hydrophobic contact with the core trimers of both HPIV3 and RSV F.

PubMed: 31951396
DOI: 10.1021/jacs.9b11548

実験手法

X-RAY DIFFRACTION (1.45 Å)