title: Structure of the Dengue virus helicase/nucleoside triphosphatase catalytic domain at a resolution of 2.4 A.
abstract: Dengue fever is an important emerging public health concern, with several million viral infections occurring annually, for which no effective therapy currently exists. The NS3 protein from Dengue virus is a multifunctional protein of 69 kDa, endowed with protease, helicase, and nucleoside 5'-triphosphatase (NTPase) activities. Thus, NS3 plays an important role in viral replication and represents a very interesting target for the development of specific antiviral inhibitors. We present the structure of an enzymatically active fragment of the Dengue virus NTPase/helicase catalytic domain to 2.4 A resolution. The structure is composed of three domains, displays an asymmetric distribution of charges on its surface, and contains a tunnel large enough to accommodate single-stranded RNA. Its C-terminal domain adopts a new fold compared to the NS3 helicase of hepatitis C virus, which has interesting implications for the evolution of the Flaviviridae replication complex. A bound sulfate ion reveals residues involved in the metal-dependent NTPase catalytic mechanism. Comparison with the NS3 hepatitis C virus helicase complexed to single-stranded DNA would place the 3' single-stranded tail of a nucleic acid duplex in the tunnel that runs across the basic face of the protein. A possible model for the unwinding mechanism is proposed.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, 60, Nanyang Drive, Singapore 637551.
authors.forename: Ting
authors.initials: T
authors.lastname: Xu
authors.forename: Aruna
authors.initials: A
authors.lastname: Sampath
authors.forename: Alex
authors.initials: A
authors.lastname: Chao
authors.forename: Daying
authors.initials: D
authors.lastname: Wen
authors.forename: Max
authors.initials: M
authors.lastname: Nanao
authors.forename: Patrick
authors.initials: P
authors.lastname: Chene
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
authors.forename: Julien
authors.initials: J
authors.lastname: Lescar
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020134:Catalytic Domain; D003460:Crystallization; D019281:Dimerization; D008958:Models, Molecular; D008969:Molecular Sequence Data; D043583:Nucleoside-Triphosphatase / Q000737:chemistry* / Q000378:metabolism / Q000502:physiology; D020365:RNA Helicases / Q000737:chemistry / Q000502:physiology; D012697:Serine Endopeptidases / Q000737:chemistry / Q000502:physiology; D017361:Viral Nonstructural Proteins / Q000737:chemistry* / Q000502:physiology; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
chemical_list: D043583:Nucleoside-Triphosphatase; D020365:RNA Helicases; D012697:Serine Endopeptidases; D017361:Viral Nonstructural Proteins; C060028:NS3 protein, flavivirus; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases