6UYD

Structure of Hepatitis C Virus Envelope Glycoprotein E2mc3-v1 redesigned core from genotype 1a bound to broadly neutralizing antibody AR3C

6UYD の概要

• エントリーDOI: 10.2210/pdb6uyd/pdb
• 分子名称: Envelope glycoprotein E2, Fab AR3C heavy chain, Fab AR3C light chain, ... (6 entities in total)
• 機能のキーワード: hcv, e2 core, vaccine design, self-assembly nanoparticle, broadly neutralizing antibodies, bnabs, viral protein-immune system complex, viral protein/immune system
• 由来する生物種: Hepatitis C virus (isolate H); 詳細
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 136523.91

構造登録者

Tzarum, N.,Wilson, I.A.,Zhu, J. (登録日: 2019-11-13, 公開日: 2020-04-22, 最終更新日: 2024-11-20)

主引用文献

He, L.,Tzarum, N.,Lin, X.,Shapero, B.,Sou, C.,Mann, C.J.,Stano, A.,Zhang, L.,Nagy, K.,Giang, E.,Law, M.,Wilson, I.A.,Zhu, J.
Proof of concept for rational design of hepatitis C virus E2 core nanoparticle vaccines.
Sci Adv, 6:eaaz6225-eaaz6225, 2020

PubMed Abstract: Hepatitis C virus (HCV) envelope glycoproteins E1 and E2 are responsible for cell entry, with E2 being the major target of neutralizing antibodies (NAbs). Here, we present a comprehensive strategy for B cell-based HCV vaccine development through E2 optimization and nanoparticle display. We redesigned variable region 2 in a truncated form (tVR2) on E2 cores derived from genotypes 1a and 6a, resulting in improved stability and antigenicity. Crystal structures of three optimized E2 cores with human cross-genotype NAbs (AR3s) revealed how the modified tVR2 stabilizes E2 without altering key neutralizing epitopes. We then displayed these E2 cores on 24- and 60-meric nanoparticles and achieved substantial yield and purity, as well as enhanced antigenicity. In mice, these nanoparticles elicited more effective NAb responses than soluble E2 cores. Next-generation sequencing (NGS) defined distinct B cell patterns associated with nanoparticle-induced antibody responses, which target the conserved neutralizing epitopes on E2 and cross-neutralize HCV genotypes.

PubMed: 32494617
DOI: 10.1126/sciadv.aaz6225

実験手法

X-RAY DIFFRACTION (1.897 Å)