View source for 3wiy


==Crystal structure of Mcl-1 in complex with compound 10==
<StructureSection load='3wiy' size='340' side='right'caption='[[3wiy]], [[Resolution|resolution]] 2.15&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[3wiy]] 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=3WIY OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3WIY 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]] 2.15&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=LC6:7-(4-{[(4-{[(2R)-4-(DIMETHYLAMINO)-1-(PHENYLSULFANYL)BUTAN-2-YL]AMINO}-3-NITROPHENYL)SULFONYL]CARBAMOYL}-2-METHYLPHENYL)-3-[3-(NAPHTHALEN-1-YLOXY)PROPYL]PYRAZOLO[1,5-A]PYRIDINE-2-CARBOXYLIC+ACID'>LC6</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=3wiy FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3wiy OCA], [https://pdbe.org/3wiy PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3wiy RCSB], [https://www.ebi.ac.uk/pdbsum/3wiy PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3wiy ProSAT]</span></td></tr>
</table>
== Function ==
[https://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).

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>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 3wiy" style="background-color:#fffaf0;"></div>

==See Also==
*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]]
== References ==
<references/>
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</StructureSection>
[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Hayano Y]]
[[Category: Igaki S]]
[[Category: Sogabe S]]