Zhang Shuijun
Email Address
gmszhsh@nus.edu.sg
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Publication Neutralization mechanism of a highly potent antibody against Zika virus(Nature Publishing Group, 2016) Zhang, S; Kostyuchenko, V.A; Ng, T.-S; Lim, X.-N; Ooi, J.S.G; Lambert, S; Tan, T.Y; Widman, D.G; Shi, J; Baric, R.S; Lok, S.-M; MICROBIOLOGY AND IMMUNOLOGY; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOLThe rapid spread of Zika virus (ZIKV), which causes microcephaly and Guillain-Barré syndrome, signals an urgency to identify therapeutics. Recent efforts to rescreen dengue virus human antibodies for ZIKV cross-neutralization activity showed antibody C10 as one of the most potent. To investigate the ability of the antibody to block fusion, we determined the cryoEM structures of the C10-ZIKV complex at pH levels mimicking the extracellular (pH8.0), early (pH6.5) and late endosomal (pH5.0) environments. The 4.0 Å resolution pH8.0 complex structure shows that the antibody binds to E proteins residues at the intra-dimer interface, and the virus quaternary structure-dependent inter-dimer and inter-raft interfaces. At pH6.5, antibody C10 locks all virus surface E proteins, and at pH5.0, it locks the E protein raft structure, suggesting that it prevents the structural rearrangement of the E proteins during the fusion event - a vital step for infection. This suggests antibody C10 could be a good therapeutic candidate. © The Author(s) 2016.Publication A Human Antibody Neutralizes Different Flaviviruses by Using Different Mechanisms(Elsevier B.V., 2020) Zhang, S.; Loy, T.; Ng, T.-S.; Lim, X.-N.; Chew, S.-Y.V.; Tan, T.Y.; Xu, M.; Kostyuchenko, V.A.; Tukijan, F.; Shi, J.; Fink, K.; Lok, S.-M.; MICROBIOLOGY AND IMMUNOLOGY; BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOLHuman antibody SIgN-3C neutralizes dengue virus (DENV) and Zika virus (ZIKV) differently. DENV:SIgN-3C Fab and ZIKV:SIgN-3C Fab cryoelectron microscopy (cryo-EM) complex structures show Fabs crosslink E protein dimers at extracellular pH 8.0 condition and also when further incubated at acidic endosomal conditions (pH 8.0–6.5). We observe Fab binding to DENV (pH 8.0–5.0) prevents virus fusion, and the number of bound Fabs increase (from 120 to 180). For ZIKV, although there are already 180 copies of Fab at pH 8.0, virus structural changes at pH 5.0 are not inhibited. The immunoglobulin G (IgG):DENV structure at pH 8.0 shows both Fab arms bind to epitopes around the 2-fold vertex. On ZIKV, an additional Fab around the 5-fold vertex at pH 8.0 suggests one IgG arm would engage with an epitope, although the other may bind to other viruses, causing aggregation. For DENV2 at pH 5.0, a similar scenario would occur, suggesting DENV2:IgG complex would aggregate in the endosome. Hence, a single antibody employs different neutralization mechanisms against different flaviviruses. Zhang et al. show that a human monoclonal antibody SIgN-3C can neutralize closely related dengue and Zika virus via different mechanisms. The antibody neutralizes dengue virus by preventing virus:endosomal membrane fusion, although it aggregates Zika virus particles extracellularly. © 2020 The Author(s)Publication High flavivirus structural plasticity demonstrated by a non-spherical morphological variant(Nature Research, 2020-06-19) Morrone, S.R.; Chew, V.S.Y.; Lim, X.-N.; Ng, T.-S.; Kostyuchenko, V.A.; Zhang, S.; Chew, P.-L.; Lee, J.; Tan, J.L.; Wang, J.; Tan, T.Y.; Shi, J.; Screaton, G.; Morais, M.C.; Lok, S.-M.; MICROBIOLOGY AND IMMUNOLOGY; BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOLPrevious flavivirus (dengue and Zika viruses) studies showed largely spherical particles either with smooth or bumpy surfaces. Here, we demonstrate flavivirus particles have high structural plasticity by the induction of a non-spherical morphology at elevated temperatures: the club-shaped particle (clubSP), which contains a cylindrical tail and a disc-like head. Complex formation of DENV and ZIKV with Fab C10 stabilize the viruses allowing cryoEM structural determination to ~10 Å resolution. The caterpillar-shaped (catSP) Fab C10:ZIKV complex shows Fabs locking the E protein raft structure containing three E dimers. However, compared to the original spherical structure, the rafts have rotated relative to each other. The helical tail structure of Fab C10:DENV3 clubSP showed although the Fab locked an E protein dimer, the dimers have shifted laterally. Morphological diversity, including clubSP and the previously identified bumpy and smooth-surfaced spherical particles, may help flavivirus survival and immune evasion. © 2020, The Author(s).Publication Capsid protein structure in Zika virus reveals the flavivirus assembly process(Nature Research, 2020) Tan, T.Y.; Fibriansah, G.; Kostyuchenko, V.A.; Ng, T.-S.; Lim, X.-X.; Zhang, S.; Lim, X.-N.; Wang, J.; Shi, J.; Morais, M.C.; Corti, D.; Lok, S.-M.; MICROBIOLOGY AND IMMUNOLOGY; DEAN'S OFFICE (DUKE-NUS MEDICAL SCHOOL); BIOLOGICAL SCIENCES; DUKE-NUS MEDICAL SCHOOLStructures of flavivirus (dengue virus and Zika virus) particles are known to near-atomic resolution and show detailed structure and arrangement of their surface proteins (E and prM in immature virus or M in mature virus). By contrast, the arrangement of the capsid proteins:RNA complex, which forms the core of the particle, is poorly understood, likely due to inherent dynamics. Here, we stabilize immature Zika virus via an antibody that binds across the E and prM proteins, resulting in a subnanometer resolution structure of capsid proteins within the virus particle. Fitting of the capsid protein into densities shows the presence of a helix previously thought to be removed via proteolysis. This structure illuminates capsid protein quaternary organization, including its orientation relative to the lipid membrane and the genomic RNA, and its interactions with the transmembrane regions of the surface proteins. Results show the capsid protein plays a central role in the flavivirus assembly process. © 2020, The Author(s).