Structural view of the helicase reveals that<i>Zika virus</i>uses a conserved mechanism for unwinding RNA

Li, Lei; Wang, Jin; Jia, Zhu; Shaw, Neil

doi:10.1107/s2053230x18003813

Cited by 7 publications

(8 citation statements)

References 38 publications

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“…Non-protein positive 2Fo -Fc electron density was attributed to water molecules. The resulting 3D protein structure shows overall similarity with already published helicase structures of other flaviviruses (10)(11)(12)(13)(14)(39)(40)(41). NS3H has a clover-shaped architecture divided into three domains containing seven conserved motifs of SF2 helicase family (Fig.…”

Section: B Tbev Ns3h Structure Is Similar To That Of Other Flavivirus...supporting

confidence: 66%

Mechanistic insight into the ATP hydrolysis cycle of tick-borne encephalitis virus helicase

Anindita¹,

Halbeisen²,

Rooney³

et al. 2022

Preprint

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Helicase domain of nonstructural protein 3 (NS3H) unwinds double-stranded RNA replication intermediate during flavivirus life cycle in ATP-dependent manner. While the helicases mechanism of Dengue and Zika viruses has been extensively studied, little is known about helicase activity of the tick-borne encephalitis virus NS3. In the current study, we demonstrated that ATP hydrolysis cycle of NS3H is strongly stimulated by ssRNA but not ssDNA, suggesting that NS3H is an RNA-specific helicase. However, ssDNA binding inhibits ATPase activity in a non-competitive manner. We also captured several structural snapshots of key ATP hydrolysis stages. An intermediate, in which the inorganic phosphate (Pi) and ADP resulted from ATP hydrolysis and remain trapped inside the ATPase site, suggests that Pi release is the rate-limiting step and is accelerated by RNA binding and/or translocation. Based on these structures, we modeled NS3H-ssRNA and -ssDNA binding and performed MD simulations. Our model suggests that NS3H-ssRNA binding triggers conformational changes, revealing the coupling between helicase and ATPase activities. The structural models revealed that ssDNA inhibition may occur via non-specific ssDNA binding to several positively charged surface patches which in turn causes repositioning of ATP molecule within the ATPase site.

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Section: B Tbev Ns3h Structure Is Similar To That Of Other Flavivirus...supporting

confidence: 66%

Mechanistic insight into the ATP hydrolysis cycle of tick-borne encephalitis virus helicase

Anindita¹,

Halbeisen²,

Rooney³

et al. 2022

Preprint

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show abstract

“…The reactant water was observed in the DENV AMPPNP-Mn/ADP-Mn structures and the ZIKV NS3_Hel-ADP-Mn structure obtained by ATP-Mn 2+ soaking but not in the ADP-vanadate-Mn structure. 10,11 In the latter structure, the site of the reactant water was occupied by the vanadate. 8 We should note that, in the ADP-P i -Mn structure, both the P i and the reactant water were modeled.…”

mentioning

confidence: 99%

“…The RNA unwinding activity of the flavivirus NS3 is coupled to adenosine triphosphate (ATP) hydrolysis. Crystallographic data, mostly from DENV NS3 and more recently from ZIKV NS3, have nearly completed the structural scheme of the ATP hydrolysis cycle. − The cycle mainly includes ATP substrate binding, hydrolysis, and the release of the adenosine diphosphate (ADP) and phosphate (P i ) products. Aside from the catalytic motifs in helicase domains 1 and 2 (D1 and D2), a divalent metal ion, naturally being Mg 2+ but typically being Mn 2+ in obtaining crystallographic data, and the reactant water (W r in figure illustrations) play pivotal roles in the hydrolysis cycle.…”

mentioning

confidence: 99%

Crystallographic Snapshots of the Zika Virus NS3 Helicase Help Visualize the Reactant Water Replenishment

Fang

Jing

et al. 2019

ACS Infect. Dis.

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Zika virus (ZIKV), a positive-strand RNA virus belonging to the Flavivirus genus, has become an urgent public health concern since recent outbreaks worldwide. Its genome replication is facilitated by the viral NS3 protein bearing helicase function. The NS3 helicase uses energy derived from adenosine triphosphate (ATP) hydrolysis to unwind RNA duplexed regions. Structural studies of the flavivirus NS3 helicases have suggested a conserved mechanism of ATP hydrolysis. However, the process of the reactant water replenishment, a key part of the hydrolysis cycle, remains elusive. Here, we report two high-resolution crystal structures of ZIKV NS3 helicase in complex with adenosine diphosphate (ADP) and Mn2+, one with the reactant water already loaded as previously observed and the other with the water molecule still in a loading state. These data suggest that the reactant water replenishment can occur between the release of phosphate and the release of ADP and improves the structural basis of the NS3 ATP hydrolysis cycle.

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“…The structure of ZIKV NS3 helicase has been reported by several groups. − ZIKV NS3 helicase is composed of three domains of roughly similar size. The structure is similar to that of the DENV2 NS3 helicase (RMSD ∼ 0.9 Å), with variability in loop regions involved in ATP and RNA binding (Figure E,G).…”

Section: Structure and Function Of Nonstructural Proteinsmentioning

confidence: 87%

Systematic Analysis of Structure Similarity between Zika Virus and Other Flaviviruses

Sun

2019

ACS Infect. Dis.

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Zika virus (ZIKV) infection has caused global concern because of its association with fetal microcephaly and serious neurological complications in adults since 2016. Currently, no specific anti-ZIKV therapy is available to control ZIKV infection. During the last couple of years, the intensive investigation of ZIKV structure has provided significant information for structure-based vaccine and drug design. In this review, we summarized the research progress on the structures of ZIKV and its component proteins. We analyzed the structure identity and the differences between ZIKV and other flaviviruses. This information is crucial to guiding structure-based anti-ZIKV inhibitors and vaccine discovery.

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Structural view of the helicase reveals thatZika virususes a conserved mechanism for unwinding RNA

Cited by 7 publications

References 38 publications

Mechanistic insight into the ATP hydrolysis cycle of tick-borne encephalitis virus helicase

Mechanistic insight into the ATP hydrolysis cycle of tick-borne encephalitis virus helicase

Crystallographic Snapshots of the Zika Virus NS3 Helicase Help Visualize the Reactant Water Replenishment

Systematic Analysis of Structure Similarity between Zika Virus and Other Flaviviruses

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