National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI076331
米国
National Institutes of Health/National Institute Of Allergy and Infectious Diseases (NIH/NIAID)
AI073755
米国
引用
ジャーナル: Viruses / 年: 2020 タイトル: Structural Basis of Zika Virus Specific Neutralization in Subsequent Flavivirus Infections. 著者: Madhumati Sevvana / Thomas F Rogers / Andrew S Miller / Feng Long / Thomas Klose / Nathan Beutler / Yen-Chung Lai / Mara Parren / Laura M Walker / Geeta Buda / Dennis R Burton / Michael G ...著者: Madhumati Sevvana / Thomas F Rogers / Andrew S Miller / Feng Long / Thomas Klose / Nathan Beutler / Yen-Chung Lai / Mara Parren / Laura M Walker / Geeta Buda / Dennis R Burton / Michael G Rossmann / Richard J Kuhn / 要旨: Zika virus (ZIKV), a mosquito-borne human flavivirus that causes microcephaly and other neurological disorders, has been a recent focus for the development of flavivirus vaccines and therapeutics. We ...Zika virus (ZIKV), a mosquito-borne human flavivirus that causes microcephaly and other neurological disorders, has been a recent focus for the development of flavivirus vaccines and therapeutics. We report here a 4.0 Å resolution structure of the mature ZIKV in complex with ADI-30056, a ZIKV-specific human monoclonal antibody (hMAb) isolated from a ZIKV infected donor with a prior dengue virus infection. The structure shows that the hMAb interactions span across the E protein dimers on the virus surface, inhibiting conformational changes required for the formation of infectious fusogenic trimers similar to the hMAb, ZIKV-117. Structure-based functional analysis, and structure and sequence comparisons, identified ZIKV residues essential for neutralization and crucial for the evolution of highly potent E protein crosslinking Abs in ZIKV. Thus, this epitope, ZIKV's "Achilles heel", defined by the contacts between ZIKV and ADI-30056, could be a suitable target for the design of therapeutic antibodies.
H: ADI30056 Fab heavy chain variable region L: ADI30056 Fab light chain variable region A: envelope protein E B: membrane protein M C: envelope protein E D: membrane protein M E: envelope protein E F: membrane protein M ヘテロ分子
H: ADI30056 Fab heavy chain variable region L: ADI30056 Fab light chain variable region A: envelope protein E B: membrane protein M C: envelope protein E D: membrane protein M E: envelope protein E F: membrane protein M ヘテロ分子
H: ADI30056 Fab heavy chain variable region L: ADI30056 Fab light chain variable region A: envelope protein E B: membrane protein M C: envelope protein E D: membrane protein M E: envelope protein E F: membrane protein M ヘテロ分子
x 5
icosahedral pentamer
1.07 MDa, 40 ポリマー
分子量 (理論値)
分子数
合計 (水以外)
1,070,884
55
ポリマ-
1,064,518
40
非ポリマー
6,366
15
水
0
タイプ
名称
対称操作
数
point symmetry operation
5
4
H: ADI30056 Fab heavy chain variable region L: ADI30056 Fab light chain variable region A: envelope protein E B: membrane protein M C: envelope protein E D: membrane protein M E: envelope protein E F: membrane protein M ヘテロ分子
x 6
icosahedral 23 hexamer
1.29 MDa, 48 ポリマー
分子量 (理論値)
分子数
合計 (水以外)
1,285,061
66
ポリマ-
1,277,422
48
非ポリマー
7,639
18
水
0
タイプ
名称
対称操作
数
point symmetry operation
6
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
ADI30056Fabheavychainvariableregion
分子量: 13467.001 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Scheffersomyces stipitis (菌類)
#2: 抗体
ADI30056Fablightchainvariableregion
分子量: 11385.728 Da / 分子数: 1 / 由来タイプ: 組換発現 / 由来: (組換発現) Homo sapiens (ヒト) / 発現宿主: Scheffersomyces stipitis (菌類)