3g76

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{{Seed}}
 
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[[Image:3g76.png|left|200px]]
 
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==Crystal structure of XIAP-BIR3 in complex with a bivalent compound==
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<StructureSection load='3g76' size='340' side='right'caption='[[3g76]], [[Resolution|resolution]] 3.00&Aring;' scene=''>
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== Structural highlights ==
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or the SCENE parameter (which sets the initial scene displayed when the page is loaded),
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<table><tr><td colspan='2'>[[3g76]] is a 8 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=3G76 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3G76 FirstGlance]. <br>
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</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&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CZ3:1,1-{HEXA-2,4-DIYNE-1,6-DIYLBIS[OXY{(2S,3R)-2-[(N-METHYL-L-ALANYL)AMINO]-1-OXOBUTANE-3,1-DIYL}(2S)PYRROLIDINE-1,2-DIYLMETHANEDIYL]}BIS[5-(PHENYLSULFANYL)-1H-TETRAZOLE]'>CZ3</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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{{STRUCTURE_3g76| PDB=3g76 | SCENE= }}
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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=3g76 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3g76 OCA], [https://pdbe.org/3g76 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3g76 RCSB], [https://www.ebi.ac.uk/pdbsum/3g76 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3g76 ProSAT]</span></td></tr>
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</table>
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== Disease ==
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[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>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/g7/3g76_consurf.spt"</scriptWhenChecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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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=3g76 ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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XIAP is an apoptotic regulator protein that binds to the effector caspases -3 and -7 through its BIR2 domain, and to initiator caspase-9 through its BIR3 domain. Molecular docking studies suggested that Smac-DIABLO may antagonize XIAP by concurrently targeting both BIR2 and BIR3 domains; on this basis bivalent Smac-mimetic compounds have been proposed and characterized. Here, we report the X-ray crystal structure of XIAP-BIR3 domain in complex with a two-headed compound (compound 3) with improved efficacy relative to its monomeric form. A small-angle X-ray scattering study of XIAP-BIR2BIR3, together with fluorescence polarization binding assays and compound 3 cytotoxicity tests on HL60 leukemia cell line are also reported. The crystal structure analysis reveals a network of interactions supporting XIAP-BIR3/compound 3 recognition; moreover, analytical gel-filtration chromatography shows that compound 3 forms a 1:1 stoichiometric complex with a XIAP protein construct containing both BIR2 and BIR3 domains. On the basis of the crystal structure and small-angle X-ray scattering, a model of the same BIR2-BIR3 construct bound to compound 3 is proposed, shedding light on the ability of compound 3 to relieve XIAP inhibitory effects on caspase-9 as well as caspases -3 and -7. A molecular modeling/docking analysis of compound 3 bound to cIAP1-BIR3 domain is presented, considering that Smac-mimetics have been shown to kill tumor cells by inducing cIAP1 and cIAP2 ubiquitination and degradation. Taken together, the results reported here provide a rationale for further development of compound 3 as a lead in the design of dimeric Smac mimetics for cancer treatment.
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===Crystal structure of XIAP-BIR3 in complex with a bivalent compound===
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Structural basis for bivalent Smac-mimetics recognition in the IAP protein family.,Cossu F, Milani M, Mastrangelo E, Vachette P, Servida F, Lecis D, Canevari G, Delia D, Drago C, Rizzo V, Manzoni L, Seneci P, Scolastico C, Bolognesi M J Mol Biol. 2009 Sep 25;392(3):630-44. Epub 2009 Apr 22. PMID:19393243<ref>PMID:19393243</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 3g76" style="background-color:#fffaf0;"></div>
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==See Also==
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The line below this paragraph, {{ABSTRACT_PUBMED_19393243}}, adds the Publication Abstract to the page
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*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
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(as it appears on PubMed at http://www.pubmed.gov), where 19393243 is the PubMed ID number.
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== References ==
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<references/>
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{{ABSTRACT_PUBMED_19393243}}
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__TOC__
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</StructureSection>
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==Disease==
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Known disease associated with this structure: Lymphoproliferative syndrome, X-linked, 2 OMIM:[[http://www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?id=300079 300079]]
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==About this Structure==
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3G76 is a 8 chains structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3G76 OCA].
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==Reference==
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<ref group="xtra">PMID:19393243</ref><references group="xtra"/>
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[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Bolognesi, M.]]
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[[Category: Large Structures]]
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[[Category: Cossu, F.]]
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[[Category: Bolognesi M]]
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[[Category: Mastrangelo, E.]]
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[[Category: Cossu F]]
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[[Category: Milani, M.]]
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[[Category: Mastrangelo E]]
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[[Category: Apoptosis]]
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[[Category: Milani M]]
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[[Category: Cytoplasm]]
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[[Category: Iap]]
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[[Category: Ligase]]
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[[Category: Metal-binding]]
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[[Category: Peptidomimetic]]
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[[Category: Phosphoprotein]]
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[[Category: Polymorphism]]
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[[Category: Pro-apoptotic drug]]
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[[Category: Protease inhibitor]]
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[[Category: Smacdiablo]]
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[[Category: Thiol protease inhibitor]]
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[[Category: Ubl conjugation]]
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[[Category: Ubl conjugation pathway]]
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[[Category: Zinc]]
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[[Category: Zinc-finger]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Wed Oct 28 14:18:19 2009''
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Current revision

Crystal structure of XIAP-BIR3 in complex with a bivalent compound

PDB ID 3g76

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