1tft
From Proteopedia
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==NMR Structure of an Antagonists of the XIAP-Caspase-9 Interaction Complexed to the BIR3 domain of XIAP== | ==NMR Structure of an Antagonists of the XIAP-Caspase-9 Interaction Complexed to the BIR3 domain of XIAP== | ||
| - | <StructureSection load='1tft' size='340' side='right'caption='[[1tft | + | <StructureSection load='1tft' size='340' side='right'caption='[[1tft]]' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>[[1tft]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/ | + | <table><tr><td colspan='2'>[[1tft]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1TFT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1TFT FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=997:1-[3,3-DIMETHYL-2-(2-METHYLAMINO-PROPIONYLAMINO)-BUTYRYL]-4-PHENOXY-PYRROLIDINE-2-CARBOXYLIC+ACID(1,2,3,4-TETRAHYDRO-NAPHTHALEN-1-YL)-AMIDE'>997</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=997:1-[3,3-DIMETHYL-2-(2-METHYLAMINO-PROPIONYLAMINO)-BUTYRYL]-4-PHENOXY-PYRROLIDINE-2-CARBOXYLIC+ACID(1,2,3,4-TETRAHYDRO-NAPHTHALEN-1-YL)-AMIDE'>997</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr> | |
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1tft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tft OCA], [https://pdbe.org/1tft PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tft RCSB], [https://www.ebi.ac.uk/pdbsum/1tft PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tft ProSAT]</span></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=1tft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1tft OCA], [https://pdbe.org/1tft PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1tft RCSB], [https://www.ebi.ac.uk/pdbsum/1tft PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1tft ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Disease == | == Disease == | ||
| - | + | [https://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN] Defects in XIAP are the cause of lymphoproliferative syndrome X-linked type 2 (XLP2) [MIM:[https://omim.org/entry/300635 300635]. XLP is a rare immunodeficiency characterized by extreme susceptibility to infection with Epstein-Barr virus (EBV). Symptoms include severe or fatal mononucleosis, acquired hypogammaglobulinemia, pancytopenia and malignant lymphoma.<ref>PMID:17080092</ref> | |
== Function == | == Function == | ||
| - | + | [https://www.uniprot.org/uniprot/XIAP_HUMAN XIAP_HUMAN] Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis. Acts as a direct caspase inhibitor. Directly bind to the active site pocket of CASP3 and CASP7 and obstructs substrate entry. Inactivates CASP9 by keeping it in a monomeric, inactive state. Acts as an E3 ubiquitin-protein ligase regulating NF-kappa-B signaling and the target proteins for its E3 ubiquitin-protein ligase activity include: RIPK1, CASP3, CASP7, CASP8, CASP9, MAP3K2/MEKK2, DIABLO/SMAC, AIFM1, CCS and BIRC5/survivin. Ubiquitinion of CCS leads to enhancement of its chaperone activity toward its physiologic target, SOD1, rather than proteasomal degradation. Ubiquitinion of MAP3K2/MEKK2 and AIFM1 does not lead to proteasomal degradation. Plays a role in copper homeostasis by ubiquitinationg COMMD1 and promoting its proteasomal degradation. Can also function as E3 ubiquitin-protein ligase of the NEDD8 conjugation pathway, targeting effector caspases for neddylation and inactivation. Regulates the BMP signaling pathway and the SMAD and MAP3K7/TAK1 dependent pathways leading to NF-kappa-B and JNK activation. Acts as an important regulator of innate immune signaling via regulation of Nodlike receptors (NLRs). Protects cells from spontaneous formation of the ripoptosome, a large multi-protein complex that has the capability to kill cancer cells in a caspase-dependent and caspase-independent manner. Suppresses ripoptosome formation by ubiquitinating RIPK1 and CASP8. Acts as a positive regulator of Wnt signaling and ubiquitinates TLE1, TLE2, TLE3, TLE4 and AES. Ubiquitination of TLE3 results in inhibition of its interaction with TCF7L2/TCF4 thereby allowing efficient recruitment and binding of the transcriptional coactivator beta-catenin to TCF7L2/TCF4 that is required to initiate a Wnt-specific transcriptional program.<ref>PMID:9230442</ref> <ref>PMID:11447297</ref> <ref>PMID:12121969</ref> <ref>PMID:14685266</ref> <ref>PMID:14645242</ref> <ref>PMID:17967870</ref> <ref>PMID:19473982</ref> <ref>PMID:21145488</ref> <ref>PMID:20154138</ref> <ref>PMID:22103349</ref> <ref>PMID:22304967</ref> <ref>PMID:17560374</ref> | |
== Evolutionary Conservation == | == Evolutionary Conservation == | ||
[[Image:Consurf_key_small.gif|200px|right]] | [[Image:Consurf_key_small.gif|200px|right]] | ||
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1tft ConSurf]. | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1tft ConSurf]. | ||
<div style="clear:both"></div> | <div style="clear:both"></div> | ||
| - | <div style="background-color:#fffaf0;"> | ||
| - | == Publication Abstract from PubMed == | ||
| - | Inhibitor of apoptosis (IAP) proteins are overexpressed in many cancers and have been implicated in tumor growth, pathogenesis, and resistance to chemo- or radiotherapy. On the basis of the NMR structure of a SMAC peptide complexed with the BIR3 domain of X-linked IAP (XIAP), a novel series of XIAP antagonists was discovered. The most potent compounds in this series bind to the baculovirus IAP repeat 3 (BIR3) domain of XIAP with single-digit nanomolar affinity and promote cell death in several human cancer cell lines. In a MDA-MB-231 breast cancer mouse xenograft model, these XIAP antagonists inhibited the growth of tumors. Close structural analogues that showed only weak binding to the XIAP-BIR3 domain were inactive in the cellular assays and showed only marginal in vivo activity. Our results are consistent with a mechanism in which ligands for the BIR3 domain of XIAP induce apoptosis by freeing up caspases. The present study validates the BIR3 domain of XIAP as a target and supports the use of small molecule XIAP antagonists as a potential therapy for cancers that overexpress XIAP. | ||
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| - | Discovery of potent antagonists of the antiapoptotic protein XIAP for the treatment of cancer.,Oost TK, Sun C, Armstrong RC, Al-Assaad AS, Betz SF, Deckwerth TL, Ding H, Elmore SW, Meadows RP, Olejniczak ET, Oleksijew A, Oltersdorf T, Rosenberg SH, Shoemaker AR, Tomaselli KJ, Zou H, Fesik SW J Med Chem. 2004 Aug 26;47(18):4417-26. PMID:15317454<ref>PMID:15317454</ref> | ||
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| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| - | </div> | ||
| - | <div class="pdbe-citations 1tft" style="background-color:#fffaf0;"></div> | ||
== References == | == References == | ||
<references/> | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| - | [[Category: | + | [[Category: Homo sapiens]] |
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
| - | [[Category: Al-Assaad | + | [[Category: Al-Assaad AS]] |
| - | [[Category: Armstrong | + | [[Category: Armstrong RC]] |
| - | [[Category: Betz | + | [[Category: Betz SF]] |
| - | [[Category: Deckwerth | + | [[Category: Deckwerth TL]] |
| - | [[Category: Elmore | + | [[Category: Elmore SW]] |
| - | [[Category: Fesik | + | [[Category: Fesik SW]] |
| - | [[Category: Meadows | + | [[Category: Meadows RP]] |
| - | [[Category: Olejniczak | + | [[Category: Olejniczak ET]] |
| - | [[Category: Oleksijew | + | [[Category: Oleksijew AK]] |
| - | [[Category: Oltersdorf | + | [[Category: Oltersdorf T]] |
| - | [[Category: Oost | + | [[Category: Oost TK]] |
| - | [[Category: Rosenberg | + | [[Category: Rosenberg SH]] |
| - | [[Category: Shoemaker | + | [[Category: Shoemaker AR]] |
| - | [[Category: Sun | + | [[Category: Sun C]] |
| - | [[Category: Zou | + | [[Category: Zou H]] |
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Revision as of 08:40, 1 May 2024
NMR Structure of an Antagonists of the XIAP-Caspase-9 Interaction Complexed to the BIR3 domain of XIAP
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Categories: Homo sapiens | Large Structures | Al-Assaad AS | Armstrong RC | Betz SF | Deckwerth TL | Elmore SW | Fesik SW | Meadows RP | Olejniczak ET | Oleksijew AK | Oltersdorf T | Oost TK | Rosenberg SH | Shoemaker AR | Sun C | Zou H
