Zika virus (ZIKV) has emerged as major health concern, as ZIKV infection has been shown to be associated with microcephaly, severe neurological disease and possibly male sterility. As the largest protein component within the ZIKV replication complex, NS5 plays key roles in the life cycle and survival of the virus through its N‐terminal methyltransferase (MTase) and C‐terminal RNA‐dependent RNA polymerase (RdRp) domains. Here, we present the crystal structures of ZIKV NS5 MTase in complex with an RNA cap analogue (m7GpppA) and the free NS5 RdRp. We have identified the conserved features of ZIKV NS5 MTase and RdRp structures that could lead to development of current antiviral inhibitors being used against flaviviruses, including dengue virus and West Nile virus, to treat ZIKV infection. These results should inform and accelerate the structure‐based design of antiviral compounds against ZIKV.
The crystal structures of ZIKV NS5 MTase in complex with an RNA cap analogue (m7GpppA) and the free NS5 RdRp reveal conserved features of ZIKV MTase and RdRp structures that will aid in the structure‐based design of antiviral compounds against ZIKV.
Crystal structure of Brazilian ZIKV NS5 MTase bound to S‐adenosyl‐L‐methionine (SAM) reveals a conserved SAM‐binding pocket.
The tertiary complex structure of ZIKV MTase with SAM and RNA analogue (m7GpppA) reveals both conserved and specific features on the cap‐binding site for antiviral inhibitor design.
ZIKV NS5 RdRp structure reveals a tighter and more closed conformation compared to other flaviviruses.
ZIKV NS5 RdRp possesses conserved drug binding sites including the RNA template entry tunnel and N‐pocket, implicating current available drugs targeting Dengue virus RdRp should be tested for anti‐ZIKV activity.
The EMBO Journal (2017) 36: 919–933
- Received December 4, 2016.
- Revision received January 16, 2017.
- Accepted February 2, 2017.
- © 2017 The Authors
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