9IY0

anti-HEV mAb 8H3

9IY0 の概要

• エントリーDOI: 10.2210/pdb9iy0/pdb
• 分子名称: Light chain of 8H3 Fab, Heavy chain of 8H3 Fab, MAGNESIUM ION, ... (4 entities in total)
• 機能のキーワード: monoclonal antibody, immune system
• 由来する生物種: Mus sp.; 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 47934.51

構造登録者

Minghua, Z.,Lizhi, Z.,Yang, H.,Ying, G.,Shaowei, L. (登録日: 2024-07-29, 公開日: 2024-09-04, 最終更新日: 2025-09-10)

主引用文献

Zheng, M.,Zhou, L.,Huang, Y.,Zhang, X.,Yu, Z.,Yang, C.,Chen, Y.,Ying, D.,Wang, H.,Chen, Z.,Liu, C.,Tang, Z.,Wang, S.,Wang, K.,Yang, K.,Lin, Y.,Li, T.,Zheng, Q.,Zheng, Z.,Zhang, J.,Yu, H.,Li, S.,Gu, Y.,Xia, N.
Structural basis for the synergetic neutralization of hepatitis E virus by antibody-antibody interaction.
Proc.Natl.Acad.Sci.USA, 121:e2408585121-e2408585121, 2024

PubMed Abstract: Neutralizing antibodies (nAbs) play a crucial role in virology, antibody drug development, and vaccine research. In this study, we investigated the synergistic effect of two hepatitis E virus (HEV) nAbs, 8H3, and 8C11, which have exhibited enhanced neutralizing activity in a rhesus monkey model. We presented crystal structures of 8H3 Fab alone and a triple complex of 8C11 Fab and 8H3 Fab simultaneously binding to the HEV E2s protein (8C11:E2s:8H3). Through structural analysis, we identified critical binding sites and fully elucidated the binding footprints of nAb 8H3 in the 8C11:E2s:8H3 complex using site-directed mutagenesis, pinpointing Ile 529, Glu 549, Lys 554, and Ser 566 in the E2s domain, and K66H, S67H, D88H in the 8C11 heavy chain. Interestingly, the synergetic enhancement of 8C11 to 8H3 converted to an antagonistic effect when 8C11 bound to E2s with pretreatment of 8H3, indicating a unidirectional synergistic effect associated with the sequence of antibody involvement. We demonstrated this phenomenon through structural comparisons of E2s:8C11 vs. 8C11:E2s:8H3 crystal structures and molecular dynamics simulations, found that Ile 529 played a key role in the synergistic interplay between these two nAbs. The two-antibody combination showed a more potent antibody-imposed physical disruption mechanism and enhanced coneutralization in an authentic HEV-based cell model. Our study suggests a strategy for synergistic antibody cocktail design with antibody-antibody side-by-side interaction.

PubMed: 39585981
DOI: 10.1073/pnas.2408585121

実験手法

X-RAY DIFFRACTION (1.97 Å)