View source for 6ey2


==Crystal structure of XIAP-BIR3 in complex with a cIAP1-selective SM==
<StructureSection load='6ey2' size='340' side='right'caption='[[6ey2]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6ey2]] 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=6EY2 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6EY2 FirstGlance]. <br>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=C3T:(3~{S},6~{S},7~{S},9~{a}~{S})-~{N}-[(4-~{tert}-butylphenyl)methyl]-7-(hydroxymethyl)-6-[[(2~{S})-2-(methylamino)butanoyl]amino]-5-oxidanylidene-1,2,3,6,7,8,9,9~{a}-octahydropyrrolo[1,2-a]azepine-3-carboxamide'>C3T</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></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=6ey2 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6ey2 OCA], [https://pdbe.org/6ey2 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6ey2 RCSB], [https://www.ebi.ac.uk/pdbsum/6ey2 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6ey2 ProSAT]</span></td></tr>
</table>
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== Publication Abstract from PubMed ==
IAPs (Inhibitor of Apoptosis Proteins) are highly conserved negative regulators of apoptosis overexpressed in many cancer cells. Based on their endogenous antagonist, Smac/DIABLO, mimic compounds (Smac-mimetics, SMs) have been developed to inhibit IAPs pro-survival activity, showing promising effects in advanced phases of clinical trials. Since different IAP homologues play distinctive roles in cancer cell survival and immunomodulation, SM-induced apoptosis proceeds through diverse mechanisms. After binding to their BIR3 domain, SMs have been shown to rapidly induce auto-ubiquitylation and degradation of cellular IAPs (cIAPs), thus leading to cell death mainly by activation of the non-canonical NF-kappaB pathway. For this reason, we started the BIR3-driven design of compounds selective for cIAP1 and with reduced affinity for X-linked IAP (XIAP), in order to focus SMs anti-tumor activity on cIAPs degradation. In this work, we describe the crystal structures of the BIR3 domains of cIAP1 and XIAP, each in complex with a cIAP1-selective SM (SM130 and SM114, respectively). The two SMs displayed 23- and 32-fold higher affinity for cIAP1-BIR3 over XIAP-BIR3 in molecular displacement experiments based on fluorescence polarization. In vitro cell-based assays confirmed that both selective SMs triggered apoptosis in cancer cells with different efficiencies by inducing caspases-3, -8 and -9-independent cIAP1 degradation. The design of cIAPs-selective compounds represents an innovative approach in the field of anti-cancer drugs development, being useful to elucidate different pro-survival mechanisms, and to reduce the adverse effects of pan-IAPs compounds in cancer therapy. This article is protected by copyright. All rights reserved.

Structure-based design and molecular profiling of Smac-mimetics selective for cellular IAPs.,Corti A, Milani M, Lecis D, Seneci P, de Rosa M, Mastrangelo E, Cossu F FEBS J. 2018 Jul 28. doi: 10.1111/febs.14616. PMID:30055105<ref>PMID:30055105</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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<div class="pdbe-citations 6ey2" style="background-color:#fffaf0;"></div>

==See Also==
*[[Ubiquitin protein ligase 3D structures|Ubiquitin protein ligase 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Corti A]]
[[Category: Cossu F]]
[[Category: Mastrangelo E]]
[[Category: Milani M]]