Binding of a potent small-molecule inhibitor of six-helix bundle formation requires interactions with both heptad-repeats of the RSV fusion protein.
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.
Roymans
Dirk
D
Tibotec BVBA, B-2800 Mechelen, Belgium. droymans@its.jnj.com
De Bondt
Hendrik L
HL
Arnoult
Eric
E
Geluykens
Peggy
P
Gevers
Tom
T
Van Ginderen
Marcia
M
Verheyen
Nick
N
Kim
Hidong
H
Willebrords
Rudy
R
Bonfanti
Jean-François
JF
Bruinzeel
Wouter
W
Cummings
Maxwell D
MD
van Vlijmen
Herman
H
Andries
Koen
K
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*
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