3TJE

Crystal structure of Fas receptor extracellular domain in complex with Fab E09

Summary for 3TJE

• Entry DOI: 10.2210/pdb3tje/pdb
• Related: 3THM
• Descriptor: Fab E09, light chain, Fab E09, heavy chain, Tumor necrosis factor receptor superfamily member 6, ... (7 entities in total)
• Functional Keywords: agonistic antibody, fab fragment, antibody-receptor complex, tumor necrosis factor receptor, cysteine-rich domain, fas, immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted. Isoform 3: Secreted. Isoform 4: Secreted. Isoform 5: Secreted. Isoform 6: Secreted: P25445
• Total number of polymer chains: 3
• Total formula weight: 67221.12

Authors

Zuger, S.,Stirnimann, C.,Briand, C.,Grutter, M.G. (deposition date: 2011-08-24, release date: 2012-05-09, Last modification date: 2024-10-16)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (1.93 Å)