The solution structure of the N-terminal proteinase domain of the hepatitis C virus (HCV) NS3 protein provides new insights into its activation and catalytic mechanism.
The solution structure of the hepatitis C virus (BK strain) NS3 protein N-terminal domain (186 residues) has been solved by NMR spectroscopy. The protein is a serine protease with a chymotrypsin-type fold, and is involved in the maturation of the viral polyprotein. Despite the knowledge that its activity is enhanced by the action of a viral protein cofactor, NS4A, the mechanism of activation is not yet clear. The analysis of the folding in solution and the differences from the crystallographic structures allow the formulation of a model in which, in addition to the NS4A cofactor, the substrate plays an important role in the activation of the catalytic mechanism. A unique structural feature is the presence of a zinc-binding site exposed on the surface, subject to a slow conformational exchange process.
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IRBM "P. Angeletti", Via Pontina km 30.600, Pomezia, Roma, 00040, Italy.
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Nardi
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Steinkühler
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Cortese
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De Francesco
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Bazzo
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D000595:Amino Acid Sequence; D002384:Catalysis; D003196:Computer Graphics; D017124:Conserved Sequence; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D004926:Escherichia coli; D016174:Hepacivirus / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D012996:Solutions; D013816:Thermodynamics; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000378:metabolism*; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D011994:Recombinant Proteins; 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