National Research Foundation Investigatorship award
NRF-NRFI2016-01
シンガポール
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI100625 and AI 107731
米国
引用
ジャーナル: Nat Commun / 年: 2016 タイトル: Neutralization mechanism of a highly potent antibody against Zika virus. 著者: Shuijun Zhang / Victor A Kostyuchenko / Thiam-Seng Ng / Xin-Ni Lim / Justin S G Ooi / Sebastian Lambert / Ter Yong Tan / Douglas G Widman / Jian Shi / Ralph S Baric / Shee-Mei Lok / 要旨: The 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 ...The 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.
A: structural protein E C: structural protein E B: structural protein E G: C10 IgG heavy chain variable region H: C10 IgG light chain variable region K: C10 IgG heavy chain variable region L: C10 IgG light chain variable region I: C10 IgG heavy chain variable region M: C10 IgG light chain variable region
A: structural protein E C: structural protein E B: structural protein E G: C10 IgG heavy chain variable region H: C10 IgG light chain variable region K: C10 IgG heavy chain variable region L: C10 IgG light chain variable region I: C10 IgG heavy chain variable region M: C10 IgG light chain variable region
A: structural protein E C: structural protein E B: structural protein E G: C10 IgG heavy chain variable region H: C10 IgG light chain variable region K: C10 IgG heavy chain variable region L: C10 IgG light chain variable region I: C10 IgG heavy chain variable region M: C10 IgG light chain variable region
x 5
icosahedral pentamer
1.05 MDa, 45 ポリマー
分子量 (理論値)
分子数
合計 (水以外)
1,047,830
45
ポリマ-
1,047,830
45
非ポリマー
0
0
水
0
タイプ
名称
対称操作
数
identity operation
1_555
x,y,z
1
point symmetry operation
4
4
A: structural protein E C: structural protein E B: structural protein E G: C10 IgG heavy chain variable region H: C10 IgG light chain variable region K: C10 IgG heavy chain variable region L: C10 IgG light chain variable region I: C10 IgG heavy chain variable region M: C10 IgG light chain variable region
x 6
icosahedral 23 hexamer
1.26 MDa, 54 ポリマー
分子量 (理論値)
分子数
合計 (水以外)
1,257,396
54
ポリマ-
1,257,396
54
非ポリマー
0
0
水
0
タイプ
名称
対称操作
数
identity operation
1_555
x,y,z
1
point symmetry operation
5
5
登録構造と同一(異なる座標系)
icosahedral asymmetric unit, std point frame
タイプ
名称
対称操作
数
transform to point frame
1
6
A: structural protein E C: structural protein E B: structural protein E G: C10 IgG heavy chain variable region H: C10 IgG light chain variable region K: C10 IgG heavy chain variable region L: C10 IgG light chain variable region I: C10 IgG heavy chain variable region M: C10 IgG light chain variable region