6JHT

The cryo-EM structure of HAV bound to a neutralizing antibody-F9

6JHT の概要

• エントリーDOI: 10.2210/pdb6jht/pdb
• EMDBエントリー: 9830
• 分子名称: VP1, VP2, VP3, ... (5 entities in total)
• 機能のキーワード: icosahedral symmetry, neutralizing antibody, hav, complex, virus
• 由来する生物種: Human hepatitis A virus Hu/Australia/HM175/1976; 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 130631.04

構造登録者

Cao, L.,Liu, P.,Yang, P.,Gao, Q.,Li, H.,Sun, Y.,Zhu, L.,Lin, J.,Su, D.,Rao, Z.,Wang, X. (登録日: 2019-02-19, 公開日: 2020-03-18, 最終更新日: 2024-11-13)

主引用文献

Cao, L.,Liu, P.,Yang, P.,Gao, Q.,Li, H.,Sun, Y.,Zhu, L.,Lin, J.,Su, D.,Rao, Z.,Wang, X.
Structural basis for neutralization of hepatitis A virus informs a rational design of highly potent inhibitors.
Plos Biol., 17:e3000229-e3000229, 2019

PubMed Abstract: Hepatitis A virus (HAV), an enigmatic and ancient pathogen, is a major causative agent of acute viral hepatitis worldwide. Although there are effective vaccines, antivirals against HAV infection are still required, especially during fulminant hepatitis outbreaks. A more in-depth understanding of the antigenic characteristics of HAV and the mechanisms of neutralization could aid in the development of rationally designed antiviral drugs targeting HAV. In this paper, 4 new antibodies-F4, F6, F7, and F9-are reported that potently neutralize HAV at 50% neutralizing concentration values (neut50) ranging from 0.1 nM to 0.85 nM. High-resolution cryo-electron microscopy (cryo-EM) structures of HAV bound to F4, F6, F7, and F9, together with results of our previous studies on R10 fragment of antigen binding (Fab)-HAV complex, shed light on the locations and nature of the epitopes recognized by the 5 neutralizing monoclonal antibodies (NAbs). All the epitopes locate within the same patch and are highly conserved. The key structure-activity correlates based on the antigenic sites have been established. Based on the structural data of the single conserved antigenic site and key structure-activity correlates, one promising drug candidate named golvatinib was identified by in silico docking studies. Cell-based antiviral assays confirmed that golvatinib is capable of blocking HAV infection effectively with a 50% inhibitory concentration (IC50) of approximately 1 μM. These results suggest that the single conserved antigenic site from complete HAV capsid is a good antiviral target and that golvatinib could function as a lead compound for anti-HAV drug development.

PubMed: 31039149
DOI: 10.1371/journal.pbio.3000229

実験手法

ELECTRON MICROSCOPY (3.79 Å)