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PDBsum entry 4n90
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Apoptosis/immune system
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PDB id
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4n90
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Contents |
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108 a.a.
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155 a.a.
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214 a.a.
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218 a.a.
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PDB id:
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| Name: |
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Apoptosis/immune system
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Title:
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Crystal structure of ternary complex of trail, dr5, and fab fragment from a dr5 agonist antibody
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Structure:
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Tumor necrosis factor receptor superfamily member 10b. Chain: r, s, t. Fragment: unp residues 57-182. Synonym: death receptor 5, tnf-related apoptosis-inducing ligand receptor 2, trail receptor 2, trail-r2. Engineered: yes. Tumor necrosis factor ligand superfamily member 10. Chain: a, b, c. Fragment: unp residues 114-281.
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Source:
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Homo sapiens. Human. Organism_taxid: 9606. Gene: tnfrsf10b, dr5, killer, trailr2, trick2, ztnfr9, unq160/pro186. Expressed in: escherichia coli. Expression_system_taxid: 562. Gene: tnfsf10, apo2l, trail. Organism_taxid: 9606
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Resolution:
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3.30Å
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R-factor:
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0.229
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R-free:
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0.286
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Authors:
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X.Huang
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Key ref:
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J.D.Graves
et al.
(2014).
Apo2L/TRAIL and the death receptor 5 agonist antibody AMG 655 cooperate to promote receptor clustering and antitumor activity.
Cancer Cell,
26,
177-189.
PubMed id:
DOI:
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Date:
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18-Oct-13
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Release date:
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03-Sep-14
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PROCHECK
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Headers
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References
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O14763
(TR10B_HUMAN) -
Tumor necrosis factor receptor superfamily member 10B from Homo sapiens
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Seq:
Struc:
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440 a.a.
108 a.a.
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P50591
(TNF10_HUMAN) -
Tumor necrosis factor ligand superfamily member 10 from Homo sapiens
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Seq:
Struc:
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281 a.a.
155 a.a.
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DOI no:
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Cancer Cell
26:177-189
(2014)
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PubMed id:
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Apo2L/TRAIL and the death receptor 5 agonist antibody AMG 655 cooperate to promote receptor clustering and antitumor activity.
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J.D.Graves,
J.J.Kordich,
T.H.Huang,
J.Piasecki,
T.L.Bush,
T.Sullivan,
I.N.Foltz,
W.Chang,
H.Douangpanya,
T.Dang,
J.W.O'Neill,
R.Mallari,
X.Zhao,
D.G.Branstetter,
J.M.Rossi,
A.M.Long,
X.Huang,
P.M.Holland.
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ABSTRACT
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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.
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Links
