3KPE

Solution structure of the respiratory syncytial virus (RSV)six-helix bundle complexed with TMC353121, a small-moleucule inhibitor of RSV

3KPE の概要

• エントリーDOI: 10.2210/pdb3kpe/pdb
• 分子名称: Fusion glycoprotein F0, 2-[[6-[[[2-(3-hydroxypropyl)-5-methylphenyl]amino]methyl]-2-[[3-(4-morpholinyl)propyl]amino]-1H-benzimidazol-1-yl]methyl]-6-methyl-3-pyridinol, TETRAETHYLENE GLYCOL, ... (5 entities in total)
• 機能のキーワード: peptide-small-molecule complex, alpha helix, coiled-coil, envelope protein, fusion protein, glycoprotein, host cell membrane, host membrane, lipoprotein, membrane, palmitate, transmembrane, virion, viral protein
• 由来する生物種: Human respiratory syncytial virus; 詳細
• 細胞内の位置: Virion membrane; Single-pass type I membrane protein: P03420 P03420
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 10660.26

構造登録者

Roymans, D.,De Bondt, H.,Arnoult, E.,Cummings, M.D.,Van Vlijmen, H.,Andries, K. (登録日: 2009-11-16, 公開日: 2009-12-22, 最終更新日: 2023-09-06)

主引用文献

Roymans, D.,De Bondt, H.L.,Arnoult, E.,Geluykens, P.,Gevers, T.,Van Ginderen, M.,Verheyen, N.,Kim, H.,Willebrords, R.,Bonfanti, J.F.,Bruinzeel, W.,Cummings, M.D.,van Vlijmen, H.,Andries, K.
Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein.
Proc.Natl.Acad.Sci.USA, 107:308-313, 2010

PubMed Abstract: Six-helix bundle (6HB) formation is an essential step for many viruses that rely on a class I fusion protein to enter a target cell and initiate replication. Because the binding modes of small molecule inhibitors of 6HB formation are largely unknown, precisely how they disrupt 6HB formation remains unclear, and structure-based design of improved inhibitors is thus seriously hampered. Here we present the high resolution crystal structure of TMC353121, a potent inhibitor of respiratory syncytial virus (RSV), bound at a hydrophobic pocket of the 6HB formed by amino acid residues from both HR1 and HR2 heptad-repeats. Binding of TMC353121 stabilizes the interaction of HR1 and HR2 in an alternate conformation of the 6HB, in which direct binding interactions are formed between TMC353121 and both HR1 and HR2. Rather than completely preventing 6HB formation, our data indicate that TMC353121 inhibits fusion by causing a local disturbance of the natural 6HB conformation.

PubMed: 19966279
DOI: 10.1073/pnas.0910108106

実験手法

X-RAY DIFFRACTION (1.47 Å)