3wix: Difference between revisions

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{{STRUCTURE_3wix| PDB=3wix |  SCENE= }}
==Crystal structure of Mcl-1 in complex with compound 4==
===Crystal structure of Mcl-1 in complex with compound 4===
<StructureSection load='3wix' size='340' side='right' caption='[[3wix]], [[Resolution|resolution]] 1.90&Aring;' scene=''>
{{ABSTRACT_PUBMED_24215352}}
== Structural highlights ==
<table><tr><td colspan='2'>[[3wix]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WIX OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3WIX FirstGlance]. <br>
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LC3:7-(4-CARBOXYPHENYL)-3-[3-(NAPHTHALEN-1-YLOXY)PROPYL]PYRAZOLO[1,5-A]PYRIDINE-2-CARBOXYLIC+ACID'>LC3</scene></td></tr>
<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3wiy|3wiy]], [[3wiz|3wiz]]</td></tr>
<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">MCL1, BCL2L3 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3wix FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wix OCA], [http://www.rcsb.org/pdb/explore.do?structureId=3wix RCSB], [http://www.ebi.ac.uk/pdbsum/3wix PDBsum]</span></td></tr>
</table>
== Function ==
[[http://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>  
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
Mcl-1 and Bcl-xL are crucial regulators of apoptosis, therefore dual inhibitors of both proteins could serve as promising new anticancer drugs. To design Mcl-1/Bcl-xL dual inhibitors, we performed structure-guided analyses of the corresponding selective Mcl-1 and Bcl-xL inhibitors. A co-crystal structure of a pyrazolo[1,5-a]pyridine derivative with Mcl-1 protein was successfully determined and revealed the protein-ligand binding mode. The key structure for Bcl-xL inhibition was further confirmed through the substructural analysis of ABT-263, a representative Bcl-xL/Bcl-2/Bcl-w inhibitor developed by Abbott Laboratories. Based on the structural data from this analysis, we designed hybrid compounds by tethering the Mcl-1 and Bcl-xL inhibitors together. The results of X-ray crystallographic analysis of hybrid compound 10 in complexes with both Mcl-1 and Bcl-xL demonstrated its binding mode with each protein. Following further optimization, compound 11 showed potent Mcl-1/Bcl-xL dual inhibitory activity (Mcl-1, IC50 = 0.088 muM; and Bcl-xL, IC50 = 0.0037 muM).


==Function==
Discovery of Potent Mcl-1/Bcl-xL Dual Inhibitors by Using a Hybridization Strategy Based on Structural Analysis of Target Proteins.,Tanaka Y, Aikawa K, Nishida G, Homma M, Sogabe S, Igaki S, Hayano Y, Sameshima T, Miyahisa I, Kawamoto T, Tawada M, Imai Y, Inazuka M, Cho N, Imaeda Y, Ishikawa T J Med Chem. 2013 Nov 11. PMID:24215352<ref>PMID:24215352</ref>
[[http://www.uniprot.org/uniprot/MCL1_HUMAN MCL1_HUMAN]] Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.<ref>PMID:10766760</ref>


==About this Structure==
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
[[3wix]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3WIX OCA].
</div>


==Reference==
==See Also==
<ref group="xtra">PMID:024215352</ref><references group="xtra"/><references/>
*[[Bcl-2|Bcl-2]]
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Human]]
[[Category: Human]]
[[Category: Hayano, Y.]]
[[Category: Hayano, Y]]
[[Category: Igaki, S.]]
[[Category: Igaki, S]]
[[Category: Sogabe, S.]]
[[Category: Sogabe, S]]
[[Category: Apoptosis]]
[[Category: Apoptosis]]
[[Category: Regulation]]
[[Category: Regulation]]
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