3KPE

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

Summary for 3KPE

• Entry DOI: 10.2210/pdb3kpe/pdb
• Descriptor: 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)
• Functional Keywords: 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
• Biological source: Human respiratory syncytial virus; More
• Cellular location: Virion membrane; Single-pass type I membrane protein: P03420 P03420
• Total number of polymer chains: 2
• Total formula weight: 10660.26

Authors

Roymans, D.,De Bondt, H.,Arnoult, E.,Cummings, M.D.,Van Vlijmen, H.,Andries, K. (deposition date: 2009-11-16, release date: 2009-12-22, Last modification date: 2023-09-06)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.47 Å)