2i3h: Difference between revisions

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New page: left|200px<br /> <applet load="2i3h" size="450" color="white" frame="true" align="right" spinBox="true" caption="2i3h, resolution 1.62Å" /> '''Structure of an ML-...
 
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[[Image:2i3h.gif|left|200px]]<br />
<applet load="2i3h" size="450" color="white" frame="true" align="right" spinBox="true"
caption="2i3h, resolution 1.62&Aring;" />
'''Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)'''<br />


==Overview==
==Structure of an ML-IAP/XIAP chimera bound to a 4-mer peptide (AVPW)==
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.
<StructureSection load='2i3h' size='340' side='right'caption='[[2i3h]], [[Resolution|resolution]] 1.62&Aring;' scene=''>
 
== Structural highlights ==
==About this Structure==
<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>
2I3H is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with ZN, LI, BTB and EDO as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=2I3H OCA].
</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>
 
<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>
==Reference==
<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>
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://ispc.weizmann.ac.il//pmbin/getpm?pmid=17168540 17168540]
</table>
== Function ==
[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>
== Evolutionary Conservation ==
[[Image:Consurf_key_small.gif|200px|right]]
Check<jmol>
  <jmolCheckbox>
    <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/i3/2i3h_consurf.spt"</scriptWhenChecked>
    <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
    <text>to colour the structure by Evolutionary Conservation</text>
  </jmolCheckbox>
</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].
<div style="clear:both"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Fairbrother, W.J.]]
[[Category: Fairbrother WJ]]
[[Category: Franklin, M.C.]]
[[Category: Franklin MC]]
[[Category: BTB]]
[[Category: EDO]]
[[Category: LI]]
[[Category: ZN]]
[[Category: apoptosis inhibition]]
[[Category: drug design]]
[[Category: peptide complex]]
[[Category: peptidomimetic]]
[[Category: small molecule]]
[[Category: zinc binding]]
 
''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 22:40:15 2007''

Latest revision as of 09:01, 21 February 2024

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

2i3h, resolution 1.62Å

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