The Structural Basis Of Non-structural Protein YFV NS1 And Anti-NS1 Antibody

Yellow fever virus(YFV)belongs to Flavivirus of Flaviviridae.Flavivirus is the largest and typical genus,which include Zika virus,Dengue virus,West Nile virus and Tickborne Encephalitis virus.Yellow fever virus is a typical species in Flavivirus.In 2016,yellow fever cases that imported in China become a threat to public safety along with the outbreak of zika virus.The appearance of YFV in China and the outbreak of zika virus worldwide lead us to re-examine the possibility of yellow fever transmission in China.NS1 protein of yellow fever virus is the first non-structural protein of yellow fever virus and plays an important role in virus replication.However,the C-terminal structure of yellow fever virus NS1 makes NS1 form homologous dimer,and in the study of Zika virus,we found that the C-terminal electrification of ZIKV NS1 is different from that of DENV NS1,which may affect the structure of the virus.At the same time,NS1 antibodies targeting DENV are somewhat protective against dengue virus,so whether specific antibodies targeting YFV NS1 are protective is another mystery.In this study,through the structure of YFV NS1_172-352 found that two YFV NS1_172-352 formed a homologous dimers by head-to-head.NS1 protein has two faces,one is a ladder face,another face is loop face formed by many anti-parallel loops.The surface area of YFV NS1_172-352 dimer is about 1327A²,which is much smaller than the surface area of ZIKV NS1_172-352protein(1628A²).Compared-the interaction force between YFV NS1_172-352 dimer and ZIKV NS1_172-352 dimer,it was found that the change of YFV NS1_172-352 on amino acids T233G and K228L weakened the hydrogen bond and salt bridge action.In addition,W232 was missing in YFV NS1,which was only found in YFV but not in other flavivirus.Moreover,this deficiency leads to the weakening of hydrophobic action,which may reduce the stability of dimer.At the same time,studies on antibodies that can bind to YFV NS1_172-352 showed that the antibody targeting YFV NS1_172-352 did not play a preventive or therapeutic role.Due to DENV NS1-specified antibodies have protective effects,which suggests that the structural differences between YFV NS1_172-352 and DENV NS1_172-352 may lead to the fact that the less effect of antibody targeting YFV NS1.Together,YFV NS1may be not a good target for antibody development,indicating that caution should be taken in the selection and development of antibodies targeting YFV NS1_172-352.At the same time,the binding region of the antibody 3B5 and YFV NS1_172-352 was mapped on the NS1 hexamer of DENV2.It was found that the binding of 3B5 antibody to secreted NS1 may be sterically hindered,resulting in insufficient binding and decreased affinity of the two.This may be related to the lack of protective effect of 3B5 antibodies.