4N90

Crystal structure of ternary complex of TRAIL, DR5, and Fab fragment from a DR5 agonist antibody

Summary for 4N90

• Entry DOI: 10.2210/pdb4n90/pdb
• Descriptor: Tumor necrosis factor receptor superfamily member 10B, Tumor necrosis factor ligand superfamily member 10, Fab light chain, ... (5 entities in total)
• Functional Keywords: dr5, trail, agonist, antibody, cooperation, clustering, apoptosis-immune system complex, apoptosis/immune system
• Biological source: Homo sapiens (human); More
• Cellular location: Membrane; Single-pass type I membrane protein: O14763; Membrane; Single-pass type II membrane protein (Potential): P50591
• Total number of polymer chains: 12
• Total formula weight: 242778.05

Authors

Huang, X. (deposition date: 2013-10-18, release date: 2014-09-03)

Primary citation

Graves, J.D.,Kordich, J.J.,Huang, T.H.,Piasecki, J.,Bush, T.L.,Sullivan, T.,Foltz, I.N.,Chang, W.,Douangpanya, H.,Dang, T.,O'Neill, J.W.,Mallari, R.,Zhao, X.,Branstetter, D.G.,Rossi, J.M.,Long, A.M.,Huang, X.,Holland, P.M.
Apo2L/TRAIL and the Death Receptor 5 Agonist Antibody AMG 655 Cooperate to Promote Receptor Clustering and Antitumor Activity.
Cancer Cell, 26:177-189, 2014

PubMed Abstract: Death receptor agonist therapies have exhibited limited clinical benefit to date. Investigations into why Apo2L/TRAIL and AMG 655 preclinical data were not predictive of clinical response revealed that coadministration of Apo2L/TRAIL with AMG 655 leads to increased antitumor activity in vitro and in vivo. The combination of Apo2L/TRAIL and AMG 655 results in enhanced signaling and can sensitize Apo2L/TRAIL-resistant cells. Structure determination of the Apo2L/TRAIL-DR5-AMG 655 ternary complex illustrates how higher order clustering of DR5 is achieved when both agents are combined. Enhanced agonism generated by combining Apo2L/TRAIL and AMG 655 provides insight into the limited efficacy observed in previous clinical trials and suggests testable hypotheses to reconsider death receptor agonism as a therapeutic strategy.

PubMed: 25043603
DOI: 10.1016/j.ccr.2014.04.028

Experimental method

X-RAY DIFFRACTION (3.3 Å)