9ORE

CryoEM structure of 4F11 Fab bound to stabilized MPV-2c HMPV preF

これはPDB形式変換不可エントリーです。

9ORE の概要

• エントリーDOI: 10.2210/pdb9ore/pdb
• EMDBエントリー: 70773
• 分子名称: Fusion glycoprotein F0, 4F11 Heavy Chain, 4F11 Light Chain, ... (6 entities in total)
• 機能のキーワード: immune system, hmpv, prefusion f, antibody, site 0, glycan dependent
• 由来する生物種: human metapneumovirus; 詳細
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 175619.04

構造登録者

McGovern, M.R.,Pancera, M. (登録日: 2025-05-21, 公開日: 2025-07-30, 最終更新日: 2026-02-11)

主引用文献

Harris, E.D.,McGovern, M.,Pernikoff, S.,Ikeda, R.,Kipnis, L.,Hannon, W.,Sobolik, E.B.,Gray, M.,Greninger, A.L.,He, S.,Chin, C.N.,Fu, T.M.,Pancera, M.,Boonyaratanakornkit, J.
DEVELOPMENT OF A POTENT MONOCLONAL ANTIBODY FOR TREATMENT OF HUMAN METAPNEUMOVIRUS INFECTIONS.
Biorxiv, 2025

PubMed Abstract: Human metapneumovirus (HMPV) is a major cause of respiratory infections, particularly among vulnerable populations, yet effective therapeutics remain unavailable. Monoclonal antibodies (mAbs) offer a promising approach for both treatment and prevention. Here, we describe the discovery and characterization of 4F11, a highly potent and broadly neutralizing mAb with demonstrated in vitro and in vivo efficacy against HMPV. Using cryo-electron microscopy, we defined a unique mechanism of binding HMPV employed by 4F11, which distinguishes it from previously characterized RSV and HMPV mAbs. 4F11 targets an epitope located at the apex of the prefusion F protein (site Ø) with a 1:1 stoichiometry, distinct from the 3:1 stoichiometry observed with other HMPV site Ø antibodies. Unlike other site Ø antibodies, which penetrate the glycan shield between Asn57 and Asn172, 4F11 binds vertically and directly interacts with the Asn172 glycan, representing a unique glycan-dependent mode of recognition. In vitro, 4F11 displayed high potency and broad neutralization across diverse HMPV strains. It also showed a low propensity for resistance development, with only a single escape mutation (K179E) identified, a mutation not found in any published HMPV sequence to date. Viruses rescued with the K179E escape mutation had significantly decreased fitness in vitro compared to wild-type virus. In a hamster challenge model, 4F11 significantly reduced viral loads in both the lungs and nasal turbinates. These findings highlight 4F11 as a promising candidate for therapeutic development, particularly for immunocompromised individuals and other high-risk groups.

PubMed: 40666860
DOI: 10.1101/2025.06.09.657676

実験手法

ELECTRON MICROSCOPY (4.13 Å)