3THM

Crystal structure of Fas receptor extracellular domain in complex with Fab EP6b_B01

3THM の概要

• エントリーDOI: 10.2210/pdb3thm/pdb
• 関連するPDBエントリー: 3TJE
• 分子名称: Fab EP6b_B01, light chain, Fab EP6b_B01, heavy chain, Tumor necrosis factor receptor superfamily member 6, ... (6 entities in total)
• 機能のキーワード: agonistic antibody, fab fragment, antibody-receptor complex, tumor necrosis factor receptor, cysteine-rich domain, fas, immune system
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 67705.36

構造登録者

Zuger, S.,Stirnimann, C.,Briand, C.,Grutter, M.G. (登録日: 2011-08-19, 公開日: 2012-05-09, 最終更新日: 2024-11-06)

主引用文献

Chodorge, M.,Zuger, S.,Stirnimann, C.,Briand, C.,Jermutus, L.,Grutter, M.G.,Minter, R.R.
A series of Fas receptor agonist antibodies that demonstrate an inverse correlation between affinity and potency.
Cell Death Differ., 19:1187-1195, 2012

PubMed Abstract: Receptor agonism remains poorly understood at the molecular and mechanistic level. In this study, we identified a fully human anti-Fas antibody that could efficiently trigger apoptosis and therefore function as a potent agonist. Protein engineering and crystallography were used to mechanistically understand the agonistic activity of the antibody. The crystal structure of the complex was determined at 1.9 Å resolution and provided insights into epitope recognition and comparisons with the natural ligand FasL (Fas ligand). When we affinity-matured the agonist antibody, we observed that, surprisingly, the higher-affinity antibodies demonstrated a significant reduction, rather than an increase, in agonist activity at the Fas receptor. We propose and experimentally demonstrate a model to explain this non-intuitive impact of affinity on agonist antibody signalling and explore the implications for the discovery of therapeutic agonists in general.

PubMed: 22261618
DOI: 10.1038/cdd.2011.208

実験手法

X-RAY DIFFRACTION (2.1 Å)