6TKE

ChiLob 7/4 H2 HC-C224S Kappa LC-C214S F(ab')2

This is a non-PDB format compatible entry.

Summary for 6TKE

• Entry DOI: 10.2210/pdb6tke/pdb
• Descriptor: ChiLob 7/4 H2 heavy chain C224S, ChiLob 7/4 H2 kappa chain C214S (3 entities in total)
• Functional Keywords: ----, immune system
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 2
• Total formula weight: 48546.90

Authors

Orr, C.M.,Fisher, H.,Tews, I. (deposition date: 2019-11-28, release date: 2021-06-09, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.35 Å)