The structure of Zika virus NS5 reveals a conserved domain conformation

Wang, Boxiao; Tan, Xiao -Feng; Thurmond, Stephanie; Zhang, Zhi -Min; Lin, Asher; Hai, Rong; Song, Jikui

doi:10.1038/ncomms14763

Title: The structure of Zika virus NS5 reveals a conserved domain conformation

Abstract

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.

Authors:

Wang, Boxiao ^[1]; Tan, Xiao -Feng ^[1]; Thurmond, Stephanie ^[1]; Zhang, Zhi -Min ^[1]; Lin, Asher ^[1]; Hai, Rong ^[1]; Song, Jikui ^[1]

Univ. of California, Riverside, CA (United States)

Publication Date:: Mon Mar 27 00:00:00 EDT 2017

Research Org.:: Univ. of California, Riverside, CA (United States)

Sponsoring Org.:: USDOE Office of Science (SC), Basic Energy Sciences (BES)

OSTI Identifier:: 1361212

Grant/Contract Number:: AC02-05CH11231

Resource Type:: Accepted Manuscript

Journal Name:: Nature Communications

Additional Journal Information:: Journal Volume: 8; Journal ID: ISSN 2041-1723

Publisher:: Nature Publishing Group

Country of Publication:: United States

Language:: English

Subject:: 60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; drug discovery; X-ray crystallography

Citation Formats


                    Wang, Boxiao, Tan, Xiao -Feng, Thurmond, Stephanie, Zhang, Zhi -Min, Lin, Asher, Hai, Rong, and Song, Jikui. The structure of Zika virus NS5 reveals a conserved domain conformation.  United States: N. p., 2017. 
Web.  doi:10.1038/ncomms14763.

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                    Wang, Boxiao, Tan, Xiao -Feng, Thurmond, Stephanie, Zhang, Zhi -Min, Lin, Asher, Hai, Rong, & Song, Jikui. The structure of Zika virus NS5 reveals a conserved domain conformation.  United States.  https://doi.org/10.1038/ncomms14763

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                    Wang, Boxiao, Tan, Xiao -Feng, Thurmond, Stephanie, Zhang, Zhi -Min, Lin, Asher, Hai, Rong, and Song, Jikui. Mon .  
"The structure of Zika virus NS5 reveals a conserved domain conformation".  United States.  https://doi.org/10.1038/ncomms14763.  https://www.osti.gov/servlets/purl/1361212.

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@article{osti_1361212,

  title        = {The structure of Zika virus NS5 reveals a conserved domain conformation},

  author       = {Wang, Boxiao and Tan, Xiao -Feng and Thurmond, Stephanie and Zhang, Zhi -Min and Lin, Asher and Hai, Rong and Song, Jikui},

  abstractNote = {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.},

  doi          = {10.1038/ncomms14763},

  journal      = {Nature Communications},

  number       = ,

  volume       = 8,

  place        = {United States},

  year         = {Mon Mar 27 00:00:00 EDT 2017},

  month        = {Mon Mar 27 00:00:00 EDT 2017}

}

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https://doi.org/10.1038/ncomms14763

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Cited by: 77 works

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Figures / Tables:

Figure 1 : Structural overview of ZIKV NS5. (a) Colour-coded domain architecture of ZIKV NS5. (b) Orthogonal views of ribbon (left) and electrostatic surface (right) representations of ZIKV NS5. The MTase domain, the N-terminal extension, palm, fingers, priming loop and thumb of the RdRp domain, and the interdomain linker aremore »

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Works referenced in this record:

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Title: The structure of Zika virus NS5 reveals a conserved domain conformation

Abstract

Citation Formats

Figures / Tables:

Zika virus in the Americas: Early epidemiological and genetic findings journal, March 2016

Zika Virus journal, April 2016

An Infectious cDNA Clone of Zika Virus to Study Viral Virulence, Mosquito Transmission, and Antiviral Inhibitors journal, June 2016

The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain journal, September 2014

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The dengue virus NS5 protein as a target for drug discovery journal, July 2015

Crystal Structure of the Full-Length Japanese Encephalitis Virus NS5 Reveals a Conserved Methyltransferase-Polymerase Interface journal, August 2013

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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

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

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

Development of a fluorescence-based method for the rapid determination of Zika virus polymerase activity and the screening of antiviral drugs journal, April 2019

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

Zika Virus: Origins, Pathological Action, and Treatment Strategies journal, January 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

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

Zika virus in the Americas: Early epidemiological and genetic findings
journal, March 2016

Zika Virus
journal, April 2016

An Infectious cDNA Clone of Zika Virus to Study Viral Virulence, Mosquito Transmission, and Antiviral Inhibitors
journal, June 2016

The methyltransferase domain of dengue virus protein NS5 ensures efficient RNA synthesis initiation and elongation by the polymerase domain
journal, September 2014

Mouse STAT2 Restricts Early Dengue Virus Replication
journal, November 2010

Inhibition of Interferon-Stimulated JAK-STAT Signaling by a Tick-Borne Flavivirus and Identification of NS5 as an Interferon Antagonist
journal, October 2005

Zika Virus Targets Human STAT2 to Inhibit Type I Interferon Signaling
journal, June 2016

The Interferon Signaling Antagonist Function of Yellow Fever Virus NS5 Protein Is Activated by Type I Interferon
journal, September 2014

Flavivirus Antagonism of Type I Interferon Signaling Reveals Prolidase as a Regulator of IFNAR1 Surface Expression
journal, July 2015

Dengue Virus NS5 Inhibits Interferon‐α Signaling by Blocking Signal Transducer and Activator of Transcription 2 Phosphorylation
journal, October 2009

Dengue Virus Co-opts UBR4 to Degrade STAT2 and Antagonize Type I Interferon Signaling
journal, March 2013

The dengue virus NS5 protein as a target for drug discovery
journal, July 2015

Crystal Structure of the Full-Length Japanese Encephalitis Virus NS5 Reveals a Conserved Methyltransferase-Polymerase Interface
journal, August 2013

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

A comparison of viral RNA-dependent RNA polymerases
journal, February 2006

Structures of NS5 Methyltransferase from Zika Virus
journal, September 2016

Dengue Virus Nonstructural Protein 5 Adopts Multiple Conformations in Solution
journal, July 2012

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

Phaser crystallographic software
journal, July 2007

PHENIX : building new software for automated crystallographic structure determination
journal, October 2002

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

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

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

Development of a fluorescence-based method for the rapid determination of Zika virus polymerase activity and the screening of antiviral drugs
journal, April 2019

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

Zika Virus: Origins, Pathological Action, and Treatment Strategies
journal, January 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

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