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3wix

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Revision as of 03:02, 5 August 2016

Crystal structure of Mcl-1 in complex with compound 4

Structural highlights

3wix is a 4 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:
Related:	3wiy, 3wiz
Gene:	MCL1, BCL2L3 (HUMAN)
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

[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.^[1]

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^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Bingle CD, Craig RW, Swales BM, Singleton V, Zhou P, Whyte MK. Exon skipping in Mcl-1 results in a bcl-2 homology domain 3 only gene product that promotes cell death. J Biol Chem. 2000 Jul 21;275(29):22136-46. PMID:10766760 doi:10.1074/jbc.M909572199
↑ 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. Discovery of Potent Mcl-1/Bcl-xL Dual Inhibitors by Using a Hybridization Strategy Based on Structural Analysis of Target Proteins. J Med Chem. 2013 Nov 11. PMID:24215352 doi:http://dx.doi.org/10.1021/jm401170c

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/3wix"

@@ Line 1: / Line 1: @@
 ==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=''>
@@ Line 6: / Line 7: @@
 <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>
+<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://pdbe.org/3wix PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3wix RCSB], [http://www.ebi.ac.uk/pdbsum/3wix PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3wix ProSAT]</span></td></tr>
 </table>
 == Function ==
@@ Line 18: / Line 19: @@
 From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
 </div>
+<div class="pdbe-citations 3wix" style="background-color:#fffaf0;"></div>
 ==See Also==

3wix

From Proteopedia

Revision as of 03:02, 5 August 2016

Crystal structure of Mcl-1 in complex with compound 4

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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