5DMI

Structure of the extracellular domain of the CD40 in complex with CHI220 FAB

Summary for 5DMI

• Entry DOI: 10.2210/pdb5dmi/pdb
• Related: 5DMJ
• Descriptor: Tumor necrosis factor receptor superfamily member 5, Chi220 Fab heavy chain, Chi220 Fab light chain, ... (5 entities in total)
• Functional Keywords: cell surface receptor, antibody-antigen complex, antitumor, immune system-signaling protein complex, immune system/signaling protein
• Biological source: Homo sapiens (Human); More
• Cellular location: Isoform I: Cell membrane; Single-pass type I membrane protein. Isoform II: Secreted: P25942
• Total number of polymer chains: 3
• Total formula weight: 67547.32

Authors

Sheriff, S. (deposition date: 2015-09-08, release date: 2016-06-01, Last modification date: 2024-10-23)

Primary citation

Yamniuk, A.P.,Suri, A.,Krystek, S.R.,Tamura, J.,Ramamurthy, V.,Kuhn, R.,Carroll, K.,Fleener, C.,Ryseck, R.,Cheng, L.,An, Y.,Drew, P.,Grant, S.,Suchard, S.J.,Nadler, S.G.,Bryson, J.W.,Sheriff, S.
Functional Antagonism of Human CD40 Achieved by Targeting a Unique Species-Specific Epitope.
J.Mol.Biol., 428:2860-2879, 2016

PubMed Abstract: Current clinical anti-CD40 biologic agents include both antagonist molecules for the treatment of autoimmune diseases and agonist molecules for immuno-oncology, yet the relationship between CD40 epitope and these opposing biological outcomes is not well defined. This report describes the identification of potent antagonist domain antibodies (dAbs) that bind to a novel human CD40-specific epitope that is divergent in the CD40 of nonhuman primates. A similarly selected anti-cynomolgus CD40 dAb recognizing the homologous epitope is also a potent antagonist. Mutagenesis, biochemical, and X-ray crystallography studies demonstrate that the epitope is distinct from that of CD40 agonists. Both the human-specific and cynomolgus-specific molecules remain pure antagonists even when formatted as bivalent Fc-fusion proteins, making this an attractive therapeutic format for targeting hCD40 in autoimmune indications.

PubMed: 27216500
DOI: 10.1016/j.jmb.2016.05.014

Experimental method

X-RAY DIFFRACTION (3.69 Å)