6EDG

Pseudomonas exotoxin A domain III T18H477L

6EDG の概要

• エントリーDOI: 10.2210/pdb6edg/pdb
• 分子名称: Exotoxin, N~2~,N~2~-DIMETHYL-N~1~-(6-OXO-5,6-DIHYDROPHENANTHRIDIN-2-YL)GLYCINAMIDE (3 entities in total)
• 機能のキーワード: transferase
• 由来する生物種: Pseudomonas aeruginosa
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 23092.57

構造登録者

Moss, D.L.,Park, H.W.,Mettu, R.R.,Landry, S.J. (登録日: 2018-08-09, 公開日: 2019-02-06, 最終更新日: 2023-10-11)

主引用文献

Moss, D.L.,Park, H.W.,Mettu, R.R.,Landry, S.J.
Deimmunizing substitutions in Pseudomonasexotoxin domain III perturb antigen processing without eliminating T-cell epitopes.
J.Biol.Chem., 294:4667-4681, 2019

PubMed Abstract: Effective adaptive immune responses depend on activation of CD4+ T cells via the presentation of antigen peptides in the context of major histocompatibility complex (MHC) class II. The structure of an antigen strongly influences its processing within the endolysosome and potentially controls the identity of peptides that are presented to T cells. A recombinant immunotoxin, comprising exotoxin A domain III (PE-III) from and a cancer-specific antibody fragment, has been developed to manage cancer, but its effectiveness is limited by the induction of neutralizing antibodies. Here, we observed that this immunogenicity is substantially reduced by substituting six residues within PE-III. Although these substitutions targeted T-cell epitopes, we demonstrate that reduced conformational stability and protease resistance were responsible for the reduced antibody titer. Analysis of mouse T-cell responses coupled with biophysical studies on single-substitution versions of PE-III suggested that modest but comprehensible changes in T-cell priming can dramatically perturb antibody production. The most strongly responsive PE-III epitope was well-predicted by a structure-based algorithm. In summary, single-residue substitutions can drastically alter the processing and immunogenicity of PE-III but have only modest effects on CD4+ T-cell priming in mice. Our findings highlight the importance of structure-based processing constraints for accurate epitope prediction.

PubMed: 30683694
DOI: 10.1074/jbc.RA118.006704

実験手法

X-RAY DIFFRACTION (1.47 Å)