Structural Study Of Zika Virus Methyltransferase

At the beginning of 2015,Zika virus infection broke out in south America and spread rapidly throughout the world.In Brazil,the most serious area with Zika virus infection,there were a large number of newborns with fetal microcephaly which were finally proved to be associated with Zika virus infection.In addition to causing fetal microcephaly,ZIKV may also causes eyes abnormalities,what's more,Guillain-Barrésyndrome could happen in some cases.ZIKV causes a serious threat to the life of the patient and the development of the local area.But currently there was no effective treatment to flaviviruses including Zika virus.So it's urgent to carry out the basic research of Zika virus protein.By analyzing the high resolution crystal structure of the key protein of Zika virus,providing insight into the elegant methylation process,which will benefit the following antiviral drug development.The methyltransferase domain of ZIKV nonstructural protein 5 can sequentially methylate guanine N-7 and ribose 2?-O to form ^m7NGpppA^2?Om cap structure in the new RNA transcripts.The methylation step is crucial for ZIKV replication cycle and evading the host immune system,defects in MTase are lethal for flaviviruses,which makes MTase a potential target for rational drug design against flaviviruses.Productive replication of flaviviruses is linked with their ability to block IFN induction and signaling.The NS5 of Zika virus binds to STAT2,and causes degradation of STAT2 by the proteasome.While the level of STAT2 were significantly lower in cells expression the MTase domain than the cells expression the polymerase domain.NS5 is the key viral determinant for STAT2 degradation and it interacts with STAT2 through its MTase domain.Therefore,the research of the MTase domain is important for elucidate the RNA capping mechanisms,and exploring the specific ways to evade the IFN response.We present the 1.76?crystal structure of ZIKV MTase in complex with the byproduct SAH,the comparison of these structures at high resolution provides accurate details to elaborate the stepwise catalytic mechanism for flavivirus MTase,also the structure of ZIKV-MTase-SIN providing the structural basis for rational drug design against ZIKV and other flaviviruses.