Structure of the NS3 helicase from Zika virus

Jain, Rinku; Coloma, Javier Pardo de Santayana y; García‐Sastre, Adolfo; Aggarwal, Aneel K.

doi:10.1038/nsmb.3258

Cited by 94 publications

(85 citation statements)

References 24 publications

(29 reference statements)

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“…NS3 helicase presents two binding sites, one encompasses the RNA strand and the other is where the ATP molecule binds (Fig. 2b) [17]. The full-length NS5 protein contains two domains, representing distinct targets: the NS5 methyltransferase and NS5 polymerase [18].…”

Section: Structural Features Of Zikv Proteinsmentioning

confidence: 99%

The A–Z of Zika drug discovery

Mottin

Borba

Braga

et al. 2018

Drug Discovery Today

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Section: Structural Features Of Zikv Proteinsmentioning

confidence: 99%

The A–Z of Zika drug discovery

Mottin

Borba

Braga

et al. 2018

Drug Discovery Today

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“…Furthermore the NS3 helicases of DENV, ZIKV and JEV are all highly conserved, with this peptide occupying a similar position in all crystal structures (25,(29)(30)(31). Thus KIR2DS2 recognizes highly conserved peptide motifs, within the helicases of the Flaviviridae, which are directly involved in RNA binding and under extreme constraints on their ability to mutate.…”

Section: Kir2ds2 Recognizes Conserved Peptides From Flavivirus Helicasesmentioning

confidence: 99%

KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C

et al. 2017

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This is the author accepted manuscript (AAM). The final published version (version of record) is available online via AAAS at http://immunology.sciencemag.org/content/2/15/eaal5296. Please refer to any applicable terms of use of the publisher. University of Bristol -Explore Bristol Research General rightsThis document is made available in accordance with publisher policies. Please cite only the published version using the reference above. KIR2DS2, an activating natural killer cell receptor recognizes highly conserved peptides derived from the RNA helicases of pathogenic flaviviruses. AbstractKiller cell immunoglobulin-like receptors (KIR) are rapidly evolving species-specific natural killer cell receptors associated with protection against multiple different human viral infections. We report that the activating receptor KIR2DS2 directly recognizes viral peptides derived from conserved regions of flaviviral superfamily 2 RNA helicases in the context of MHC class I. The peptide LNPSVAATL, from the HCV helicase, binds HLA-C*0102 leading to NK cell activation through engagement of KIR2DS2. Similarly, HLA-C*0102 presents highly conserved peptides from the helicase motif 1b region of related flaviviruses, including dengue, Zika, yellow fever and Japanese encephalitis viruses, to KIR2DS2. These flaviviral peptides all contain an "MCHAT" motif, which is present in 61 out of 63 flaviviruses.LNPSVAATL is also highly conserved across HCV genotypes and mutation of this epitope is poorly tolerated by HCV. KIR2DS2 recognizes endogenously presented helicase peptides and KIR2DS2 is sufficient to inhibit HCV and dengue virus replication in the context of HLA-C*0102. Targeting short, but highly conserved, viral peptides provide non-rearranging innate immune receptors with an efficient mechanism to recognize multiple, highly variable pathogenic RNA viruses.4

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“…The apo structure of ZIKV NS3 helicase at 1.80 and 1.62 Å resolution has been reported recently (19,20). In addition, the complex structures of ZIKV helicase–MnATP 2− and ZIKV helicase–RNA reported by Tian et al .…”

Section: Introductionmentioning

confidence: 85%

Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design

Cao¹,

Li²,

Jin³

et al. 2016

Nucleic Acids Res

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Zika virus has attracted increasing attention because of its potential for causing human neural disorders, including microcephaly in infants and Guillain–Barré syndrome. Its NS3 helicase domain plays critical roles in NTP-dependent RNA unwinding and translocation during viral replication. Our structural analysis revealed a pre-activation state of NS3 helicase in complex with GTPγS, in which the triphosphate adopts a compact conformation in the absence of any divalent metal ions. In contrast, in the presence of a divalent cation, GTPγS adopts an extended conformation, and the Walker A motif undergoes substantial conformational changes. Both features contribute to more extensive interactions between the GTPγS and the enzyme. Thus, this study provides structural evidence on the allosteric modulation of MgNTP2− on the NS3 helicase activity. Furthermore, the compact conformation of inhibitory NTP identified in this study provides precise information for the rational drug design of small molecule inhibitors for the treatment of ZIKV infection.

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Structure of the NS3 helicase from Zika virus

Cited by 94 publications

References 24 publications

The A–Z of Zika drug discovery

The A–Z of Zika drug discovery

KIR2DS2 recognizes conserved peptides derived from viral helicases in the context of HLA-C

Molecular mechanism of divalent-metal-induced activation of NS3 helicase and insights into Zika virus inhibitor design

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