6TKC

ChiLob 7/4 H2 HC-C225S F(ab')2

これはPDB形式変換不可エントリーです。

6TKC の概要

• エントリーDOI: 10.2210/pdb6tkc/pdb
• 分子名称: Chilob 7/4 H2 heavy chain C225S, Chilob 7/4 H2 kappa chain (3 entities in total)
• 機能のキーワード: ----, immune system
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 48562.97

構造登録者

Orr, C.M.,Fisher, H.,Tews, I. (登録日: 2019-11-28, 公開日: 2021-06-09, 最終更新日: 2024-11-20)

主引用文献

Orr, C.M.,Fisher, H.,Yu, X.,Chan, C.H.,Gao, Y.,Duriez, P.J.,Booth, S.G.,Elliott, I.,Inzhelevskaya, T.,Mockridge, I.,Penfold, C.A.,Wagner, A.,Glennie, M.J.,White, A.L.,Essex, J.W.,Pearson, A.R.,Cragg, M.S.,Tews, I.
Hinge disulfides in human IgG2 CD40 antibodies modulate receptor signaling by regulation of conformation and flexibility.
Sci Immunol, 7:eabm3723-eabm3723, 2022

PubMed Abstract: Antibodies protect from infection, underpin successful vaccines and elicit therapeutic responses in otherwise untreatable cancers and autoimmune conditions. The human IgG2 isotype displays a unique capacity to undergo disulfide shuffling in the hinge region, leading to modulation of its ability to drive target receptor signaling (agonism) in a variety of important immune receptors, through hitherto unexplained molecular mechanisms. To address the underlying process and reveal how hinge disulfide orientation affects agonistic activity, we generated a series of cysteine to serine exchange variants in the hinge region of the clinically relevant monoclonal antibody ChiLob7/4, directed against the key immune receptor CD40. We report how agonistic activity varies with disulfide pattern and is afforded by the presence of a disulfide crossover between F(ab) arms in the agonistic forms, independently of epitope, as observed in the determined crystallographic structures. This structural "switch" affects directly on antibody conformation and flexibility. Small-angle x-ray scattering and ensemble modeling demonstrated that the least flexible variants adopt the fewest conformations and evoke the highest levels of receptor agonism. This covalent change may be amenable for broad implementation to modulate receptor signaling in an epitope-independent manner in future therapeutics.

PubMed: 35857577
DOI: 10.1126/sciimmunol.abm3723

実験手法

X-RAY DIFFRACTION (2.3 Å)