2i3h

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[[Image:2i3h.gif|left|200px]]
 
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==Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)==
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The line below this paragraph, containing "STRUCTURE_2i3h", creates the "Structure Box" on the page.
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<StructureSection load='2i3h' size='340' side='right'caption='[[2i3h]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
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You may change the PDB parameter (which sets the PDB file loaded into the applet)
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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'>[[2i3h]] is a 4 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=2I3H OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2I3H 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]] 1.62&#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=BTB:2-[BIS-(2-HYDROXY-ETHYL)-AMINO]-2-HYDROXYMETHYL-PROPANE-1,3-DIOL'>BTB</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=LI:LITHIUM+ION'>LI</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>
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{{STRUCTURE_2i3h| PDB=2i3h | 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=2i3h FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2i3h OCA], [https://pdbe.org/2i3h PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2i3h RCSB], [https://www.ebi.ac.uk/pdbsum/2i3h PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2i3h ProSAT]</span></td></tr>
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</table>
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'''Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)'''
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== Function ==
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[https://www.uniprot.org/uniprot/BIRC7_HUMAN BIRC7_HUMAN] Apoptotic regulator capable of exerting proapoptotic and anti-apoptotic activities and plays crucial roles in apoptosis, cell proliferation, and cell cycle control. Its anti-apoptotic activity is mediated through the inhibition of CASP3, CASP7 and CASP9, as well as by its E3 ubiquitin-protein ligase activity. As it is a weak caspase inhibitor, its anti-apoptotic activity is thought to be due to its ability to ubiquitinate DIABLO/SMAC targeting it for degradation thereby promoting cell survival. May contribute to caspase inhibition, by blocking the ability of DIABLO/SMAC to disrupt XIAP/BIRC4-caspase interactions. Protects against apoptosis induced by TNF or by chemical agents such as adriamycin, etoposide or staurosporine. Suppression of apoptosis is mediated by activation of MAPK8/JNK1, and possibly also of MAPK9/JNK2. This activation depends on TAB1 and NR2C2/TAK1. In vitro, inhibits CASP3 and proteolytic activation of pro-CASP9. Isoform 1 blocks staurosporine-induced apoptosis. Isoform 2 blocks etoposide-induced apoptosis. Isoform 2 protects against natural killer (NK) cell killing whereas isoform 1 augments killing.<ref>PMID:11084335</ref> <ref>PMID:16729033</ref> <ref>PMID:17294084</ref> <ref>PMID:18034418</ref>
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== Evolutionary Conservation ==
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==Overview==
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[[Image:Consurf_key_small.gif|200px|right]]
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Designed second mitochondrial activator of caspases (Smac) mimetics based on an accessible [7,5]-bicyclic scaffold bind to and antagonize protein interactions involving the inhibitor of apoptosis (IAP) proteins, X-chromosome-linked IAP (XIAP), melanoma IAP (ML-IAP), and c-IAPs 1 and 2 (cIAP1 and cIAP2). The design rationale is based on a combination of phage-panning data, peptide binding studies, and a survey of potential isosteres. The synthesis of two scaffolds is described. These compounds bind the XIAP-baculoviral IAP repeat 3 (BIR3), cIAP1-BIR3, cIAP2-BIR3, and ML-IAP-BIR domains with submicromolar affinities. The most potent Smac mimetic binds the cIAP1-BIR3 and ML-IAP-BIR domains with a K i of 50 nM. The X-ray crystal structure of this compound bound to an ML-IAP/XIAP chimeric BIR domain protein is compared with that of a complex with a phage-derived tetrapeptide, AVPW. The structures show that these compounds bind to the Smac-binding site on ML-IAP with identical hydrogen-bonding patterns and similar hydrophobic interactions. Consistent with the structural data, coimmunoprecipitation experiments demonstrate that the compounds can effectively block Smac interactions with ML-IAP. The compounds are further demonstrated to activate caspase-3 and -7, to reduce cell viability in assays using MDA-MB-231 breast cancer cells and A2058 melanoma cells, and to enhance doxorubicin-induced apoptosis in MDA-MB-231 cells.
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Check<jmol>
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<jmolCheckbox>
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==About this Structure==
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i3/2i3h_consurf.spt"</scriptWhenChecked>
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2I3H is a [[Single protein]] structure of sequence 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=2I3H OCA].
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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==Reference==
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</jmolCheckbox>
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Design, synthesis, and biological activity of a potent Smac mimetic that sensitizes cancer cells to apoptosis by antagonizing IAPs., Zobel K, Wang L, Varfolomeev E, Franklin MC, Elliott LO, Wallweber HJ, Okawa DC, Flygare JA, Vucic D, Fairbrother WJ, Deshayes K, ACS Chem Biol. 2006 Sep 19;1(8):525-33. PMID:[http://www.ncbi.nlm.nih.gov/pubmed/17168540 17168540]
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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=2i3h ConSurf].
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<div style="clear:both"></div>
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== References ==
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<references/>
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__TOC__
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
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[[Category: Single protein]]
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[[Category: Large Structures]]
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[[Category: Fairbrother, W J.]]
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[[Category: Fairbrother WJ]]
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[[Category: Franklin, M C.]]
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[[Category: Franklin MC]]
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[[Category: Apoptosis inhibition]]
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[[Category: Drug design]]
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[[Category: Peptide complex]]
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[[Category: Peptidomimetic]]
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[[Category: Small molecule]]
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[[Category: Zinc binding]]
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''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May 4 07:01:38 2008''
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Current revision

Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)

PDB ID 2i3h

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