ジャーナル: Cell Rep / 年: 2020 タイトル: A Human Antibody Neutralizes Different Flaviviruses by Using Different Mechanisms. 著者: Shuijun Zhang / Thomas Loy / Thiam-Seng Ng / Xin-Ni Lim / Shyn-Yun Valerie Chew / Ter Yong Tan / Meihui Xu / Victor A Kostyuchenko / Farhana Tukijan / Jian Shi / Katja Fink / Shee-Mei Lok / 要旨: Human 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 ...Human 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.
G: SIgN-3C Fab heavy chain I: SIgN-3C Fab light chain B: Dengue serotype 2 E protein ectodomain A: Dengue serotype 2 E protein ectodomain C: Dengue serotype 2 E protein ectodomain H: SIgN-3C Fab heavy chain L: SIgN-3C Fab light chain J: SIgN-3C Fab heavy chain K: SIgN-3C Fab light chain
G: SIgN-3C Fab heavy chain I: SIgN-3C Fab light chain B: Dengue serotype 2 E protein ectodomain A: Dengue serotype 2 E protein ectodomain C: Dengue serotype 2 E protein ectodomain H: SIgN-3C Fab heavy chain L: SIgN-3C Fab light chain J: SIgN-3C Fab heavy chain K: SIgN-3C Fab light chain
G: SIgN-3C Fab heavy chain I: SIgN-3C Fab light chain B: Dengue serotype 2 E protein ectodomain A: Dengue serotype 2 E protein ectodomain C: Dengue serotype 2 E protein ectodomain H: SIgN-3C Fab heavy chain L: SIgN-3C Fab light chain J: SIgN-3C Fab heavy chain K: SIgN-3C Fab light chain
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)
1,049,584
45
ポリマ-
1,049,584
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
G: SIgN-3C Fab heavy chain I: SIgN-3C Fab light chain B: Dengue serotype 2 E protein ectodomain A: Dengue serotype 2 E protein ectodomain C: Dengue serotype 2 E protein ectodomain H: SIgN-3C Fab heavy chain L: SIgN-3C Fab light chain J: SIgN-3C Fab heavy chain K: SIgN-3C Fab light chain
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)
1,259,501
54
ポリマ-
1,259,501
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
対称性
点対称性: (シェーンフリース記号: I (正20面体型対称))
-
要素
#1: 抗体
SIgN-3CFabheavychain / 座標モデル: Cα原子のみ
分子量: 14448.958 Da / 分子数: 3 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 細胞株 (発現宿主): HEK293-6E / 発現宿主: Homo sapiens (ヒト)
#2: 抗体
SIgN-3CFablightchain / 座標モデル: Cα原子のみ
分子量: 11832.145 Da / 分子数: 3 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 細胞株 (発現宿主): HEK293-6E / 発現宿主: Homo sapiens (ヒト)