title: Hepatitis C virus NS3 RNA helicase domain with a bound oligonucleotide: the crystal structure provides insights into the mode of unwinding.
abstract: BACKGROUND
  Hepatitis C virus (HCV) represents a major health concern as it is responsible for a significant number of hepatitis cases worldwide. Much research has focused on the replicative enzymes of HCV as possible targets for more effective therapeutic agents. HCV NS3 helicase may provide one such suitable target. Helicases are enzymes which can unwind double-stranded regions of DNA or RNA in an ATP-dependent reaction. The structures of several helicases have been published but the structural details as to how ATP binding and hydrolysis are coupled to RNA unwinding are unknown.
  
  
  RESULTS
  The structure of the HCV NS3 RNA helicase domain complexed with a single-stranded DNA oligonucleotide has been solved to 2.2 A resolution. The protein consists of three structural domains with the oligonucleotide lying in a groove between the first two domains and the third. The first two domains have an adenylate kinase like fold, including a phosphate-binding loop in the first domain.
  
  
  CONCLUSIONS
  HCV NS3 helicase is a member of a superfamily of helicases, termed superfamily II. Residues of NS3 helicase which are conserved among superfamily II helicases line an interdomain cleft between the first two domains. The oligonucleotide binds in an orthogonal binding site and contacts relatively few conserved residues. There are no strong sequence-specific interactions with the oligonucleotide bases.
authors.affiliation: Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139-4242, USA. jkim@vpharm.com caron@vpharm.com
authors.forename: J L
authors.initials: JL
authors.lastname: Kim
authors.forename: K A
authors.initials: KA
authors.lastname: Morgenstern
authors.forename: J P
authors.initials: JP
authors.lastname: Griffith
authors.forename: M D
authors.initials: MD
authors.lastname: Dwyer
authors.forename: J A
authors.initials: JA
authors.lastname: Thomson
authors.forename: M A
authors.initials: MA
authors.lastname: Murcko
authors.forename: C
authors.initials: C
authors.lastname: Lin
authors.forename: P R
authors.initials: PR
authors.lastname: Caron
mesh_terms: D000595:Amino Acid Sequence; D017124:Conserved Sequence / Q000235:genetics; D018360:Crystallography, X-Ray; D004277:DNA, Single-Stranded / Q000737:chemistry*; D016174:Hepacivirus / Q000201:enzymology*; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D016601:RNA-Binding Proteins / Q000502:physiology; D016415:Sequence Alignment; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins / Q000737:chemistry; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D004277:DNA, Single-Stranded; D016601:RNA-Binding Proteins; D017361:Viral Nonstructural Proteins; D014764:Viral Proteins; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases