Structural basis of Zika virus helicase in recognizing its substrates

Abstract

The recent explosive outbreak of Zika virus (ZIKV) infection has been reported in South and Central America and the Caribbean. Neonatal microcephaly associated with ZIKV infection has already caused a public health emergency of international concern. No specific vaccines or drugs are currently available to treat ZIKV infection. The ZIKV helicase, which plays a pivotal role in viral RNA replication, is an attractive target for therapy. We determined the crystal structures of ZIKV helicase-ATP-Mn2+ and ZIKV helicase-RNA. This is the first structure of any flavivirus helicase bound to ATP. Comparisons with related flavivirus helicases have shown that although the critical P-loop in the active site has variable conformations among different species, it adopts an identical mode to recognize ATP/Mn2+. The structure of ZIKV helicase-RNA has revealed that upon RNA binding, rotations of the motor domains can cause significant conformational changes. Strikingly, although ZIKV and dengue virus (DENV) apo-helicases share conserved residues for RNA binding, their different manners of motor domain rotations result in distinct individual modes for RNA recognition. It suggests that flavivirus helicases could have evolved a conserved engine to convert chemical energy from nucleoside triphosphate to mechanical energy for RNA unwinding, but different motor domain rotations result in variable RNA recognition modes to adapt to individual viral replication.Electronic supplementary materialThe online version of this article (doi:10.1007/s13238-016-0293-2) contains supplementary material, which is available to authorized users.

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

“…We propose that when the helicase binds to an ssDNA, it is in a resting state as in the recently reported structure (PDB: 5GJB (21)) (Figure 5A). A free NTP can bind to the Walker A motif which results in a pre-activation state (Figure 5B).…”

“…In addition, the complex structures of ZIKV helicase–MnATP 2− and ZIKV helicase–RNA reported by Tian et al . (21) has made the mechanism of substrate recognition much clear. However, essential roles of divalent cations in the modulation of NTP binding and hydrolysis in the flavivirus family helicases remain unclear.…”

The Race To Find Antivirals for Zika Virus

“…ZIKV proteins other than NS5 also constitute potential druggable antiviral targets. This is the case with the N2B-NS3 trypsin-like serine protease, which plays a key role in virus replication by contributing to viral polyprotein processing (30), or with NS3 helicase activity (31). Due to the relevance of NS2B-NS3 function in the ZIKV life cycle, the search for inhibitors of the enzymatic activity of this complex is at the front line of antiviral discovery against ZIKV (30,(32)(33)(34).…”

Advances in research on Zika virus

“…Antiviral drug screens have been developed for the identification of inhibitors against fusogenic activity of helicase, protease activity of NS3 and E protein, methyltransferase activities of NS5, and RNA-dependent RNA polymerase, however, an advance pre-clinical development is still in progress [81] . An study has suggested that important component of viral RNA replication i.e, ZIKV helicase is an attractive target for therapy [82] .…”