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New page: left|200px<br /> <applet load="1oxn" size="450" color="white" frame="true" align="right" spinBox="true" caption="1oxn, resolution 2.20Å" /> '''Structure and Funct...
 
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[[Image:1oxn.gif|left|200px]]<br />
<applet load="1oxn" size="450" color="white" frame="true" align="right" spinBox="true"
caption="1oxn, resolution 2.20&Aring;" />
'''Structure and Function Analysis of Peptide Antagonists of Melanoma Inhibitor of Apoptosis (ML-IAP)'''<br />


==Overview==
==Structure and Function Analysis of Peptide Antagonists of Melanoma Inhibitor of Apoptosis (ML-IAP)==
Melanoma inhibitor of apoptosis (ML-IAP) is a potent anti-apoptotic, protein that is upregulated in a number of melanoma cell lines but not, expressed in most normal adult tissues. Overexpression of IAP proteins, such as ML-IAP or the ubiquitously expressed X-chromosome-linked IAP, (XIAP), in human cancers has been shown to suppress apoptosis induced by a, variety of stimuli. Peptides based on the processed N-terminus of, Smac/DIABLO can negate the ability of overexpressed ML-IAP or XIAP to, suppress drug-induced apoptosis. Such peptides have been demonstrated to, bind to the single baculovirus IAP repeat (BIR) of ML-IAP and the third, BIR of XIAP with similar high affinities (approximately 0.5 microM)., Herein, we use phage-display of naive peptide libraries and synthetic, peptides to investigate the peptide-binding properties of ML-IAP-BIR and, XIAP-BIR3. X-ray crystal structures of ML-IAP-BIR in complex with Smac-, and phage-derived peptides, together with peptide, structure-activity-relationship data, indicate that the peptides can be, modified to provide increased binding affinity and selectivity for, ML-IAP-BIR relative to XIAP-BIR3. For instance, substitution of Pro3' in, the Smac-based peptide (AVPIAQKSE) with, (2S,3S)-3-methylpyrrolidine-2-carboxylic acid [(3S)-methyl-proline], results in a peptide with 7-fold greater affinity for ML-IAP-BIR and about, 100-fold specificity for ML-IAP-BIR relative to XIAP-BIR3.
<StructureSection load='1oxn' size='340' side='right'caption='[[1oxn]], [[Resolution|resolution]] 2.20&Aring;' scene=''>
 
== Structural highlights ==
==About this Structure==
<table><tr><td colspan='2'>[[1oxn]] is a 6 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=1OXN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1OXN FirstGlance]. <br>
1OXN 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 and P33 as [http://en.wikipedia.org/wiki/ligands ligands]. Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1OXN 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]] 2.2&#8491;</td></tr>
 
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=P33:3,6,9,12,15,18-HEXAOXAICOSANE-1,20-DIOL'>P33</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=1oxn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1oxn OCA], [https://pdbe.org/1oxn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1oxn RCSB], [https://www.ebi.ac.uk/pdbsum/1oxn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1oxn ProSAT]</span></td></tr>
Structure and function analysis of peptide antagonists of melanoma inhibitor of apoptosis (ML-IAP)., Franklin MC, Kadkhodayan S, Ackerly H, Alexandru D, Distefano MD, Elliott LO, Flygare JA, Mausisa G, Okawa DC, Ong D, Vucic D, Deshayes K, Fairbrother WJ, Biochemistry. 2003 Jul 15;42(27):8223-31. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=12846571 12846571]
</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/ox/1oxn_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=1oxn ConSurf].
<div style="clear:both"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Homo sapiens]]
[[Category: Homo sapiens]]
[[Category: Single protein]]
[[Category: Large Structures]]
[[Category: Ackerly, H.]]
[[Category: Ackerly H]]
[[Category: Alexandru, D.]]
[[Category: Alexandru D]]
[[Category: Deshayes, K.]]
[[Category: Deshayes K]]
[[Category: Distefano, M.D.]]
[[Category: Distefano MD]]
[[Category: Elliott, L.O.]]
[[Category: Elliott LO]]
[[Category: Fairbrother, W.J.]]
[[Category: Fairbrother WJ]]
[[Category: Flygare, J.A.]]
[[Category: Flygare JA]]
[[Category: Franklin, M.C.]]
[[Category: Franklin MC]]
[[Category: Kadkhodayan, S.]]
[[Category: Kadkhodayan S]]
[[Category: Vucic, D.]]
[[Category: Vucic D]]
[[Category: P33]]
[[Category: ZN]]
[[Category: apoptosis inhibition]]
[[Category: peptide complex]]
[[Category: zinc binding]]
 
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Latest revision as of 08:03, 14 February 2024

Structure and Function Analysis of Peptide Antagonists of Melanoma Inhibitor of Apoptosis (ML-IAP)

1oxn, resolution 2.20Å

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