An RNA cap (nucleoside‐2′‐O‐)‐methyltransferase in the flavivirus RNA polymerase NS5: crystal structure and functional characterization
Reads0
Chats0
TLDR
The results provide a structural basis for the rational design of drugs against the emerging flaviviruses and suggest that the latter is a specific cap‐binding site.Abstract:
Viruses represent an attractive system with which to study the molecular basis of mRNA capping and its relation to the RNA transcription machinery. The RNA-dependent RNA polymerase NS5 of flaviviruses presents a characteristic motif of S-adenosyl-l-methionine-dependent methyltransferases at its N-terminus, and polymerase motifs at its C-terminus. The crystal structure of an N-terminal fragment of Dengue virus type 2 NS5 is reported at 2.4 Å resolution. We show that this NS5 domain includes a typical methyltransferase core and exhibits a (nucleoside-2′-O-)-methyltransferase activity on capped RNA. The structure of a ternary complex comprising S-adenosyl-l-homocysteine and a guanosine triphosphate (GTP) analogue shows that 54 amino acids N-terminal to the core provide a novel GTP-binding site that selects guanine using a previously unreported mechanism. Binding studies using GTP- and RNA cap-analogues, as well as the spatial arrangement of the methyltransferase active site relative to the GTP-binding site, suggest that the latter is a specific cap-binding site. As RNA capping is an essential viral function, these results provide a structural basis for the rational design of drugs against the emerging flaviviruses.read more
Citations
More filters
Flaviviridae :T he Viruses and Their Replication
TL;DR: The present research attacked the Flavivirus infection through two mechanisms: Membrane Reorganization and the Compartmentalization and Assembly and Release of Particles from Flaviv virus-infected Cells and Host Resistance to Flaviviral Infection.
Journal ArticleDOI
Unique and conserved features of genome and proteome of SARS-coronavirus, an early split-off from the coronavirus group 2 lineage.
Eric J. Snijder,Peter J. Bredenbeek,Jessika C. Dobbe,Volker Thiel,John Ziebuhr,Leo L.M. Poon,Yi Guan,Mikhail Rozanov,Willy J. M. Spaan,Alexander E. Gorbalenya +9 more
TL;DR: These newly recognized viral enzymes place the mechanism of coronavirus RNA synthesis in a completely new perspective and will be important targets for the design of antiviral strategies aimed at controlling the further spread of SARS-CoV.
Book ChapterDOI
Molecular biology of flaviviruses.
TL;DR: An overview of the molecular biology of the flaviviruses is presented, which are enveloped positive-strand RNA viruses capable of causing a number of important human diseases.
Journal ArticleDOI
SAM (dependent) I AM: the S-adenosylmethionine-dependent methyltransferase fold.
TL;DR: The S-adenosylmethionine-dependent methyltransferase enzymes share little sequence identity, but incorporate a highly conserved structural fold, and residues that bind the common cofactor are poorly conserved.
Journal ArticleDOI
Tick-borne Encephalitis Virus - A Review of an Emerging Zoonosis
Karen L. Mansfield,Nicholas Johnson,L. P. Phipps,J. R. Stephenson,Anthony R. Fooks,Tom Solomon +5 more
TL;DR: This review comprehensively reviewed TBEV, its epidemiology and pathogenesis, the clinical manifestations of TBE, along with vaccination and prevention, and the factors which may have influenced an apparent increase in the number of reported human cases each year, despite the availability of effective vaccines.
References
More filters
Journal ArticleDOI
Clustal w: improving the sensitivity of progressive multiple sequence alignment through sequence weighting, position-specific gap penalties and weight matrix choice
TL;DR: The sensitivity of the commonly used progressive multiple sequence alignment method has been greatly improved and modifications are incorporated into a new program, CLUSTAL W, which is freely available.
Book ChapterDOI
Processing of X-ray diffraction data collected in oscillation mode
Zbyszek Otwinowski,Wladek Minor +1 more
TL;DR: The methods presented in the chapter have been applied to solve a large variety of problems, from inorganic molecules with 5 A unit cell to rotavirus of 700 A diameters crystallized in 700 × 1000 × 1400 A cell.
Journal ArticleDOI
PROCHECK: a program to check the stereochemical quality of protein structures
TL;DR: The PROCHECK suite of programs as mentioned in this paper provides a detailed check on the stereochemistry of a protein structure and provides an assessment of the overall quality of the structure as compared with well refined structures of the same resolution.
Journal ArticleDOI
The CCP4 suite: programs for protein crystallography
TL;DR: The CCP4 (Collaborative Computational Project, number 4) program suite is a collection of programs and associated data and subroutine libraries which can be used for macromolecular structure determination by X-ray crystallography.
Journal ArticleDOI
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Axel T. Brunger,Axel T. Brunger,Paul D. Adams,G M Clore,W. L. DeLano,Piet Gros,R.W. Grosse-Kunstleve,R.W. Grosse-Kunstleve,Jiansheng Jiang,J. Kuszewski,Michael Nilges,Navraj S. Pannu,Randy J. Read,Luke M. Rice,Thomas Simonson,Gregory L. Warren +15 more
TL;DR: The Crystallography & NMR System (CNS) as mentioned in this paper is a software suite for macromolecular structure determination by X-ray crystallography or solution nuclear magnetic resonance (NMR) spectroscopy.