Solution structure of substrate-based ligands when bound to hepatitis C virus NS3 protease domain.
The interactions of the NS3 protease domain with inhibitors that are based on N-terminal cleavage products of peptide substrates were studied by NMR methods. Transferred nuclear Overhauser effect experiments showed that these inhibitors bind the protease in a well defined, extended conformation. Protease-induced line-broadening studies helped identify the segments of inhibitors which come into contact with the protease. A comparison of the NMR data of the free and protease-bound states suggests that these ligands undergo rigidification upon complexation. This work provides the first structure of an inhibitor when bound to NS3 protease and should be valuable for designing more potent inhibitors.
LaPlante
S R
SR
Departments of Chemistry and Biological Sciences, Boehringer Ingelheim (Canada) Ltd., Bio-Méga Research Division, Laval, Québec H7S 2G5, Canada. slaplante@lav.boehringer-ingelheim.com
Cameron
D R
DR
Aubry
N
N
Lefebvre
S
S
Kukolj
G
G
Maurice
R
R
Thibeault
D
D
Lamarre
D
D
Llinàs-Brunet
M
M
D000251:Adenosine Triphosphatases / Q000378:metabolism*; D000595:Amino Acid Sequence; D016174:Hepacivirus / Q000378:metabolism*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D020365:RNA Helicases / Q000378:metabolism*; D012697:Serine Endopeptidases / Q000378:metabolism*; D012996:Solutions; D017361:Viral Nonstructural Proteins / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D000251:Adenosine Triphosphatases; D008024:Ligands; D020365:RNA Helicases; D012697:Serine Endopeptidases; D012996:Solutions; D017361:Viral Nonstructural Proteins; C084422:NS3 protein, hepatitis C virus; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases