4n90

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

Structural highlights

4n90 is a 12 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

TR10B_HUMAN Defects in TNFRSF10B may be a cause of head and neck squamous cell carcinomas (HNSCC) [MIM:275355; also known as squamous cell carcinoma of the head and neck.

Function

TR10B_HUMAN Receptor for the cytotoxic ligand TNFSF10/TRAIL. The adapter molecule FADD recruits caspase-8 to the activated receptor. The resulting death-inducing signaling complex (DISC) performs caspase-8 proteolytic activation which initiates the subsequent cascade of caspases (aspartate-specific cysteine proteases) mediating apoptosis. Promotes the activation of NF-kappa-B. Essential for ER stress-induced apoptosis.^[1]

Publication Abstract from PubMed

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.

Apo2L/TRAIL and the Death Receptor 5 Agonist Antibody AMG 655 Cooperate to Promote Receptor Clustering and Antitumor Activity.,Graves JD, Kordich JJ, Huang TH, Piasecki J, Bush TL, Sullivan T, Foltz IN, Chang W, Douangpanya H, Dang T, O'Neill JW, Mallari R, Zhao X, Branstetter DG, Rossi JM, Long AM, Huang X, Holland PM Cancer Cell. 2014 Aug 11;26(2):177-89. doi: 10.1016/j.ccr.2014.04.028. Epub 2014 , Jul 17. PMID:25043603^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem. 2004 Oct 29;279(44):45495-502. Epub 2004 Aug 18. PMID:15322075 doi:10.1074/jbc.M406933200
↑ Graves JD, Kordich JJ, Huang TH, Piasecki J, Bush TL, Sullivan T, Foltz IN, Chang W, Douangpanya H, Dang T, O'Neill JW, Mallari R, Zhao X, Branstetter DG, Rossi JM, Long AM, Huang X, Holland PM. Apo2L/TRAIL and the Death Receptor 5 Agonist Antibody AMG 655 Cooperate to Promote Receptor Clustering and Antitumor Activity. Cancer Cell. 2014 Aug 11;26(2):177-89. doi: 10.1016/j.ccr.2014.04.028. Epub 2014 , Jul 17. PMID:25043603 doi:http://dx.doi.org/10.1016/j.ccr.2014.04.028