8W3H

Crystal structure of prefusion-stabilized RSV F protein UFCR1-iSS

これはPDB形式変換不可エントリーです。

8W3H の概要

• エントリーDOI: 10.2210/pdb8w3h/pdb
• 分子名称: Prefusion-stabilized RSV F protein UFCR1-iSS, 2-acetamido-2-deoxy-beta-D-glucopyranose, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: respiratory syncytial virus, glycoprotein, prefusion vaccine, stabilized, viral protein
• 由来する生物種: Human respiratory syncytial virus A2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56092.13

構造登録者

Lee, Y.Z.,Stanfield, R.L.,Wilson, I.A.,Zhu, J. (登録日: 2024-02-22, 公開日: 2025-01-15)

主引用文献

Lee, Y.Z.,Han, J.,Zhang, Y.N.,Ward, G.,Braz Gomes, K.,Auclair, S.,Stanfield, R.L.,He, L.,Wilson, I.A.,Zhu, J.
Rational design of uncleaved prefusion-closed trimer vaccines for human respiratory syncytial virus and metapneumovirus.
Nat Commun, 15:9939-9939, 2024

PubMed Abstract: Respiratory syncytial virus (RSV) and human metapneumovirus (hMPV) cause human respiratory diseases and are major targets for vaccine development. In this study, we design uncleaved prefusion-closed (UFC) trimers for the fusion protein (F) of both viruses by examining mutations critical to F metastability. For RSV, we assess four previous prefusion F designs, including the first and second generations of DS-Cav1, SC-TM, and 847A. We then identify key mutations that can maintain prefusion F in a native-like, closed trimeric form (up to 76%) without introducing any interprotomer disulfide bond. For hMPV, we develop a stable UFC trimer with a truncated F-F linkage and an interprotomer disulfide bond. Dozens of UFC constructs are characterized by negative-stain electron microscopy (nsEM), x-ray crystallography (11 RSV-F structures and one hMPV-F structure), and antigenic profiling. Using an optimized RSV-F UFC trimer as bait, we identify three potent RSV neutralizing antibodies (NAbs) from a phage-displayed human antibody library, with a public NAb lineage targeting sites Ø and V and two cross-pneumovirus NAbs recognizing site III. In mouse immunization, rationally designed RSV-F and hMPV-F UFC trimers induce robust antibody responses with high neutralizing titers. Our study provides a foundation for future prefusion F-based RSV and hMPV vaccine development.

PubMed: 39550381
DOI: 10.1038/s41467-024-54287-x

実験手法

X-RAY DIFFRACTION (2.25 Å)