5IHL

STRUCTURE OF THE EXTRACELLULAR DOMAIN OF THE CD40 IN COMPLEX WITH 3H56-5 DAB

Summary for 5IHL

• Entry DOI: 10.2210/pdb5ihl/pdb
• Descriptor: Tumor necrosis factor receptor superfamily member 5, 3H56-5 domain antibody (dAb), SULFATE ION (3 entities in total)
• Functional Keywords: cell surface receptor; domain antibody; antitumor; protein/protein interaction;, 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: 8
• Total formula weight: 133813.27

Authors

Sheriff, S. (deposition date: 2016-02-29, release date: 2016-06-01, Last modification date: 2024-10-16)

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 (3.3 Å)