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| | ==Crystal structure of the Fab fragment of an anti-DR5 antibody bound to DR5== | | ==Crystal structure of the Fab fragment of an anti-DR5 antibody bound to DR5== |
| - | <StructureSection load='4od2' size='340' side='right' caption='[[4od2]], [[Resolution|resolution]] 3.20Å' scene=''> | + | <StructureSection load='4od2' size='340' side='right'caption='[[4od2]], [[Resolution|resolution]] 3.20Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4od2]] is a 3 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OD2 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4OD2 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4od2]] is a 3 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4OD2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4OD2 FirstGlance]. <br> |
| - | </td></tr><tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1d0g|1d0g]]</td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 3.2Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">Death receptor 5, DR5, KILLER, TNFRSF10B, TRAILR2, TRICK2, UNQ160/PRO186, ZTNFR9 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4od2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4od2 OCA], [https://pdbe.org/4od2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4od2 RCSB], [https://www.ebi.ac.uk/pdbsum/4od2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4od2 ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4od2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4od2 OCA], [http://pdbe.org/4od2 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4od2 RCSB], [http://www.ebi.ac.uk/pdbsum/4od2 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4od2 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/TR10B_HUMAN TR10B_HUMAN]] Defects in TNFRSF10B may be a cause of head and neck squamous cell carcinomas (HNSCC) [MIM:[http://omim.org/entry/275355 275355]]; also known as squamous cell carcinoma of the head and neck. | + | [https://www.uniprot.org/uniprot/TR10B_HUMAN TR10B_HUMAN] Defects in TNFRSF10B may be a cause of head and neck squamous cell carcinomas (HNSCC) [MIM:[https://omim.org/entry/275355 275355]; also known as squamous cell carcinoma of the head and neck. |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/TR10B_HUMAN 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.<ref>PMID:15322075</ref> | + | [https://www.uniprot.org/uniprot/TR10B_HUMAN 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.<ref>PMID:15322075</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | ==See Also== | | ==See Also== |
| - | *[[Tumor necrosis factor receptor|Tumor necrosis factor receptor]] | + | *[[TRAIL|TRAIL]] |
| | + | *[[Tumor necrosis factor receptor 3D structures|Tumor necrosis factor receptor 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Compaan, D]] | + | [[Category: Large Structures]] |
| - | [[Category: Hymowitz, S G]] | + | [[Category: Compaan D]] |
| - | [[Category: Apoptosis-immune system complex]] | + | [[Category: Hymowitz SG]] |
| - | [[Category: Crd]]
| + | |
| - | [[Category: Fab fragment]]
| + | |
| - | [[Category: Igg]]
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| - | [[Category: Tnfsf]]
| + | |
| Structural highlights
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
Activation of the proapoptotic receptor death receptor5 (DR5) in various cancer cells triggers programmed cell death through the extrinsic pathway. We have generated a fully human monoclonal antibody (Apomab) that induces tumor cell apoptosis through DR5 and investigated the structural features of its interaction with DR5. Biochemical studies showed that Apomab binds DR5 tightly and selectively. X-ray crystallographic analysis of the complex between the Apomab Fab fragment and the DR5 ectodomain revealed an interaction epitope that partially overlaps with both regions of the Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand binding site. Apomab induced DR5 clustering at the cell surface and stimulated a death-inducing signaling complex containing the adaptor molecule Fas-associated death domain and the apoptosis-initiating protease caspase-8. Fc crosslinking further augmented Apomab's proapoptotic activity. In vitro, Apomab triggered apoptosis in cancer cells, while sparing normal hepatocytes even upon anti-Fc crosslinking. In vivo, Apomab exerted potent antitumor activity as a single agent or in combination with chemotherapy in xenograft models, including those based on colorectal, non-small cell lung and pancreatic cancer cell lines. These results provide structural and functional insight into the interaction of Apomab with DR5 and support further investigation of this antibody for cancer therapy.
Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5.,Adams C, Totpal K, Lawrence D, Marsters S, Pitti R, Yee S, Ross S, Deforge L, Koeppen H, Sagolla M, Compaan D, Lowman H, Hymowitz S, Ashkenazi A Cell Death Differ. 2008 Apr;15(4):751-61. doi: 10.1038/sj.cdd.4402306. Epub 2008 , Jan 25. PMID:18219321[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
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
- ↑ Adams C, Totpal K, Lawrence D, Marsters S, Pitti R, Yee S, Ross S, Deforge L, Koeppen H, Sagolla M, Compaan D, Lowman H, Hymowitz S, Ashkenazi A. Structural and functional analysis of the interaction between the agonistic monoclonal antibody Apomab and the proapoptotic receptor DR5. Cell Death Differ. 2008 Apr;15(4):751-61. doi: 10.1038/sj.cdd.4402306. Epub 2008 , Jan 25. PMID:18219321 doi:http://dx.doi.org/10.1038/sj.cdd.4402306
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