Skip to main content
U.S. Department of Energy
Office of Scientific and Technical Information

The structure of Zika virus NS5 reveals a conserved domain conformation

Journal Article · · Nature Communications
DOI:https://doi.org/10.1038/ncomms14763· OSTI ID:1361212
 [1];  [2];  [2];  [2];  [2];  [2];  [2]
  1. Univ. of California, Riverside, CA (United States); Department of Biochemistry, University of California, Riverside, Riverside, California 92521, USA
  2. Univ. of California, Riverside, CA (United States)
The recent outbreak of Zika virus (ZIKV) has imposed a serious threat to public health. Here we report the crystal structure of the ZIKV NS5 protein in complex with S-adenosyl-L-homocysteine, in which the tandem methyltransferase (MTase) and RNA-dependent RNA polymerase (RdRp) domains stack into one of the two alternative conformations of flavivirus NS5 proteins. In conclusion, the activity of this NS5 protein is verified through a de novo RdRp assay on a subgenomic ZIKV RNA template. Importantly, our structural analysis leads to the identification of a potential drug-binding site of ZIKV NS5, which might facilitate the development of novel antivirals for ZIKV.
Research Organization:
Univ. of California, Riverside, CA (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22)
Grant/Contract Number:
AC02-05CH11231
OSTI ID:
1361212
Journal Information:
Nature Communications, Journal Name: Nature Communications Vol. 8; ISSN 2041-1723
Publisher:
Nature Publishing GroupCopyright Statement
Country of Publication:
United States
Language:
English

References (38)

The dengue virus NS5 protein as a target for drug discovery journal July 2015
Mouse STAT2 Restricts Early Dengue Virus Replication journal November 2010
Flavivirus NS5 Prevents the InSTATement of IFN journal September 2014
Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression journal July 2015
An Infectious cDNA Clone of Zika Virus to Study Viral Virulence, Mosquito Transmission, and Antiviral Inhibitors journal June 2016
Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling journal June 2016
A comparison of viral RNA-dependent RNA polymerases journal February 2006
Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study journal April 2016
Dengue Virus Nonstructural Protein 5 Adopts Multiple Conformations in Solution journal July 2012
Zika Virus Outbreak on Yap Island, Federated States of Micronesia journal June 2009
Zika Virus and Birth Defects — Reviewing the Evidence for Causality journal May 2016
Dengue Virus NS5 Inhibits Interferon‐α Signaling by Blocking Signal Transducer and Activator of Transcription 2 Phosphorylation journal October 2009
The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain journal September 2014
Phaser crystallographic software journal July 2007
Zika virus in the Americas: Early epidemiological and genetic findings journal March 2016
The NS5 Protein of the Virulent West Nile Virus NY99 Strain Is a Potent Antagonist of Type I Interferon-Mediated JAK-STAT Signaling journal January 2010
Crystal Structure of the Dengue Virus RNA-Dependent RNA Polymerase Catalytic Domain at 1.85-Angstrom Resolution journal February 2007
The F1 Motif of Dengue Virus Polymerase NS5 Is Involved in Promoter-Dependent RNA Synthesis journal April 2011
Blocking of Interferon-Induced Jak-Stat Signaling by Japanese Encephalitis Virus NS5 through a Protein Tyrosine Phosphatase-Mediated Mechanism journal June 2006
A Crystal Structure of the Dengue Virus NS5 Protein Reveals a Novel Inter-domain Interface Essential for Protein Flexibility and Virus Replication journal March 2015
Potent Allosteric Dengue Virus NS5 Polymerase Inhibitors: Mechanism of Action and Resistance Profiling journal August 2016
[20] Processing of X-ray diffraction data collected in oscillation mode book January 1997
Guillain-Barré Syndrome outbreak associated with Zika virus infection in French Polynesia: a case-control study journal April 2016
Structures of NS5 Methyltransferase from Zika Virus journal September 2016
The Interferon Signaling Antagonist Function of Yellow Fever Virus NS5 Protein Is Activated by Type I Interferon journal September 2014
Zika Virus Outbreak on Yap Island, Federated States of Micronesia journal June 2009
Zika Virus journal April 2016
Zika Virus and Birth Defects — Reviewing the Evidence for Causality journal May 2016
Phaser crystallographic software journal July 2007
PHENIX : building new software for automated crystallographic structure determination journal October 2002
Coot model-building tools for molecular graphics journal November 2004
The NS5 Protein of the Virulent West Nile Virus NY99 Strain Is a Potent Antagonist of Type I Interferon-Mediated JAK-STAT Signaling journal January 2010
Crystal Structure of the Dengue Virus RNA-Dependent RNA Polymerase Catalytic Domain at 1.85-Angstrom Resolution journal February 2007
The F1 Motif of Dengue Virus Polymerase NS5 Is Involved in Promoter-Dependent RNA Synthesis journal April 2011
Blocking of Interferon-Induced Jak-Stat Signaling by Japanese Encephalitis Virus NS5 through a Protein Tyrosine Phosphatase-Mediated Mechanism journal June 2006
Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist journal October 2005
Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling journal March 2013
Crystal Structure of the Full-Length Japanese Encephalitis Virus NS5 Reveals a Conserved Methyltransferase-Polymerase Interface journal August 2013

Cited By (18)

The A–Z of Zika drug discovery journal November 2018
Identification of a Small Interface between the Methyltransferase and RNA Polymerase of NS5 that is Essential for Zika Virus Replication journal November 2018
Development of a fluorescence-based method for the rapid determination of Zika virus polymerase activity and the screening of antiviral drugs journal April 2019
Zika Virus: Origins, Pathological Action, and Treatment Strategies journal January 2019
Host-Directed Antivirals: A Realistic Alternative to Fight Zika Virus journal August 2018
Suppression of Type I Interferon Signaling by Flavivirus NS5 journal December 2018
A Comprehensive Review of the Manifestations and Pathogenesis of Zika Virus in Neonates and Adults journal September 2018
Identification of Broad-Spectrum Dengue/Zika Virus Replication Inhibitors by Functionalization of Quinoline and 2,6-Diaminopurine Scaffolds journal June 2018
Novel guanosine derivatives against Zika virus polymerase in silico journal August 2019
Structure and function of Zika virus NS5 protein: perspectives for drug design journal February 2018
Broad-spectrum agents for flaviviral infections: dengue, Zika and beyond journal May 2017
Molecular docking revealed the binding of nucleotide/side inhibitors to Zika viral polymerase solved structures journal April 2018
Nuclear localization of Zika virus NS5 contributes to suppression of type I interferon production and response journal December 2019
Extinction of Zika Virus and Usutu Virus by Lethal Mutagenesis Reveals Different Patterns of Sensitivity to Three Mutagenic Drugs journal June 2018
Polymerase Activity, Protein-Protein Interaction, and Cellular Localization of the Usutu Virus NS5 Protein journal November 2019
Supramolecular arrangement of the full-length Zika virus NS5 journal April 2019
The Potential Role of the ZIKV NS5 Nuclear Spherical-Shell Structures in Cell Type-Specific Host Immune Modulation during ZIKV Infection journal November 2019
Functional Genomics and Immunologic Tools: The Impact of Viral and Host Genetic Variations on the Outcome of Zika Virus Infection journal August 2018

Figures / Tables (5)


Similar Records

Crystal structure of full-length Zika virus NS5 protein reveals a conformation similar to Japanese encephalitis virus NS5
Journal Article · Mon Feb 20 23:00:00 EST 2017 · Acta Crystallographica. Section F, Structural Biology Communications · OSTI ID:1400315

Structure and function of the Zika virus full-length NS5 protein
Journal Article · Sun Mar 26 20:00:00 EDT 2017 · Nature Communications · OSTI ID:1409432

Structural insight and flexible features of NS5 proteins from all four serotypes of Dengue virus in solution
Journal Article · Sat Oct 31 00:00:00 EDT 2015 · Acta Crystallographica Section D Biological Crystallography · OSTI ID:1257423