4c52

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<StructureSection load='4c52' size='340' side='right'caption='[[4c52]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
<StructureSection load='4c52' size='340' side='right'caption='[[4c52]], [[Resolution|resolution]] 2.05&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
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<table><tr><td colspan='2'>[[4c52]] is a 2 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=4C52 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4C52 FirstGlance]. <br>
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<table><tr><td colspan='2'>[[4c52]] is a 2 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=4C52 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4C52 FirstGlance]. <br>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=X0D:(R)-2-(3-(3-((2,4-DIFLUOROPENYL)ETHYNYL)BENZOYL)-3-PROPYLUREIDO)-3-(ISOBUTYLTHIO)+PROPANOIC+ACID'>X0D</scene></td></tr>
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</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=X0D:(R)-2-(3-(3-((2,4-DIFLUOROPENYL)ETHYNYL)BENZOYL)-3-PROPYLUREIDO)-3-(ISOBUTYLTHIO)+PROPANOIC+ACID'>X0D</scene></td></tr>
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<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4c5d|4c5d]]</td></tr>
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4c52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c52 OCA], [https://pdbe.org/4c52 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4c52 RCSB], [https://www.ebi.ac.uk/pdbsum/4c52 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4c52 ProSAT]</span></td></tr>
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<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=4c52 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4c52 OCA], [http://pdbe.org/4c52 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4c52 RCSB], [http://www.ebi.ac.uk/pdbsum/4c52 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4c52 ProSAT]</span></td></tr>
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</table>
</table>
== Function ==
== Function ==
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[[http://www.uniprot.org/uniprot/B2CL1_HUMAN B2CL1_HUMAN]] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref> Isoform Bcl-X(S) promotes apoptosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref>
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[[https://www.uniprot.org/uniprot/B2CL1_HUMAN B2CL1_HUMAN]] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref> Isoform Bcl-X(S) promotes apoptosis.<ref>PMID:19917720</ref> <ref>PMID:21840391</ref>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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The pro-survival BCL-2 proteins are attractive yet challenging targets for medicinal chemists. Their involvement in the initiation and progression of many, if not all, tumors makes them prime targets for developing new anti-cancer therapies. We present our approach based on de novo structure-based drug design. Using known structural information from complexes engaging opposing members of the BCL-2 family of proteins, we designed peptidomimetic compounds using a benzoylurea scaffold to reproduce key interactions between these proteins. A library stemming from the initial de novo designed scaffold led to the discovery of ligands with low micromolar potency (KD = 4 muM) and selectivity for BCL-XL. These compounds bind in the canonical BH3 binding groove in a binding mode distinct from previously known BCL-2 inhibitors. The results of our study provide insight into the design of a new class of antagonists targeting a challenging class of protein-protein interactions.
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De-Novo Designed Library of Benzoylureas as Inhibitors of BCL-XL: Synthesis, Structural and Biochemical Characterization.,Brady RM, Vom A, Roy MJ, Toovey N, Smith BJ, Moss RM, Hazis E, Huang DC, Parisot JP, Yang H, Street IP, Colman PM, Czabotar PE, Baell JB, Lessene G J Med Chem. 2014 Jan 23. PMID:24456288<ref>PMID:24456288</ref>
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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</div>
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<div class="pdbe-citations 4c52" style="background-color:#fffaf0;"></div>
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==See Also==
==See Also==
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__TOC__
__TOC__
</StructureSection>
</StructureSection>
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[[Category: Human]]
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[[Category: Homo sapiens]]
[[Category: Large Structures]]
[[Category: Large Structures]]
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[[Category: Brady, R M]]
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[[Category: Brady RM]]
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[[Category: Colman, P M]]
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[[Category: Colman PM]]
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[[Category: Czabotar, P E]]
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[[Category: Czabotar PE]]
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[[Category: Lessene, G]]
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[[Category: Lessene G]]
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[[Category: Roy, M J]]
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[[Category: Roy MJ]]
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[[Category: Apoptosis]]
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Revision as of 17:27, 7 September 2022

Crystal structure of Bcl-xL in complex with benzoylurea compound (39b)

PDB ID 4c52

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