title: Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein.
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.
authors: Tibotec BVBA, B-2800 Mechelen, Belgium. droymans@its.jnj.com
authors: Dirk
authors: D
authors: Roymans
authors: Hendrik L
authors: HL
authors: De Bondt
authors: Eric
authors: E
authors: Arnoult
authors: Peggy
authors: P
authors: Geluykens
authors: Tom
authors: T
authors: Gevers
authors: Marcia
authors: M
authors: Van Ginderen
authors: Nick
authors: N
authors: Verheyen
authors: Hidong
authors: H
authors: Kim
authors: Rudy
authors: R
authors: Willebrords
authors: Jean-François
authors: JF
authors: Bonfanti
authors: Wouter
authors: W
authors: Bruinzeel
authors: Maxwell D
authors: MD
authors: Cummings
authors: Herman
authors: H
authors: van Vlijmen
authors: Koen
authors: K
authors: Andries
mesh_terms: D000595:Amino Acid Sequence; D000998:Antiviral Agents / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D001562:Benzimidazoles / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D002459:Cell Fusion; D018360:Crystallography, X-Ray; D006367:HeLa Cells; D006801:Humans; D008561:Membrane Fusion / Q000502:physiology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D020449:Repetitive Sequences, Amino Acid; D018113:Respiratory Syncytial Virus, Human / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism*; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D014760:Viral Fusion Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: C528854:2-(6-((2-(3-hydroxypropyl)-5-methylphenylamino)methyl)-2-(3-morpholin-4-ylpropylamino)benzoimidazol-1-ylmethyl)-6-methylpyridin-3-ol; D000998:Antiviral Agents; D001562:Benzimidazoles; D011725:Pyridines; D014760:Viral Fusion Proteins