6uve
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==Crystal structure of BCL-XL bound to compound 7: (R)-3-(Benzylthio)-2-(3-(4-chloro-[1,1':2',1'':3'',1'''-quaterphenyl]-4'''-carbonyl)-3-(4-methylbenzyl)ureido)propanoic acid== | ==Crystal structure of BCL-XL bound to compound 7: (R)-3-(Benzylthio)-2-(3-(4-chloro-[1,1':2',1'':3'',1'''-quaterphenyl]-4'''-carbonyl)-3-(4-methylbenzyl)ureido)propanoic acid== | ||
| - | <StructureSection load='6uve' size='340' side='right'caption='[[6uve]]' scene=''> | + | <StructureSection load='6uve' size='340' side='right'caption='[[6uve]], [[Resolution|resolution]] 2.87Å' scene=''> |
== Structural highlights == | == Structural highlights == | ||
| - | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6UVE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UVE FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[6uve]] is a 3 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=6UVE OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6UVE FirstGlance]. <br> |
| - | </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=6uve FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uve OCA], [https://pdbe.org/6uve PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uve RCSB], [https://www.ebi.ac.uk/pdbsum/6uve PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uve ProSAT]</span></td></tr> | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.87Å</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=QHV:(R)-3-(Benzylthio)-2-(3-(4-chloro-[1,1 2,1 3,1-quaterphenyl]-4-carbonyl)-3-(4-methylbenzyl)ureido)propanoic+acid'>QHV</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=6uve FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6uve OCA], [https://pdbe.org/6uve PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6uve RCSB], [https://www.ebi.ac.uk/pdbsum/6uve PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6uve ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| + | == Function == | ||
| + | [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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The BCL-2 family of proteins (including the prosurvival proteins BCL-2, BCL-XL, and MCL-1) is an important target for the development of novel anticancer therapeutics. Despite the challenges of targeting protein-protein interaction (PPI) interfaces with small molecules, a number of inhibitors (called BH3 mimetics) have entered the clinic and the BCL-2 inhibitor, ABT-199/venetoclax, is already proving transformative. For BCL-XL, new validated chemical series are desirable. Here, we outline the crystallography-guided development of a structurally distinct series of BCL-XL/BCL-2 inhibitors based on a benzoylurea scaffold, originally proposed as alpha-helix mimetics. We describe structure-guided exploration of a cryptic "p5" pocket identified in BCL-XL. This work yields novel inhibitors with submicromolar binding, with marked selectivity toward BCL-XL. Extension into the hydrophobic p2 pocket yielded the most potent inhibitor in the series, binding strongly to BCL-XL and BCL-2 (nanomolar-range half-maximal inhibitory concentration (IC50)) and displaying mechanism-based killing in cells engineered to depend on BCL-XL for survival. | ||
| + | |||
| + | Structure-Guided Development of Potent Benzoylurea Inhibitors of BCL-XL and BCL-2.,Roy MJ, Vom A, Okamoto T, Smith BJ, Birkinshaw RW, Yang H, Abdo H, White CA, Segal D, Huang DCS, Baell JB, Colman PM, Czabotar PE, Lessene G J Med Chem. 2021 Apr 27. doi: 10.1021/acs.jmedchem.0c01771. PMID:33904752<ref>PMID:33904752</ref> | ||
| + | |||
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 6uve" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Czabotar PE]] | [[Category: Czabotar PE]] | ||
[[Category: Lessene G]] | [[Category: Lessene G]] | ||
[[Category: Roy MJ]] | [[Category: Roy MJ]] | ||
Current revision
Crystal structure of BCL-XL bound to compound 7: (R)-3-(Benzylthio)-2-(3-(4-chloro-[1,1':2',1:3,1-quaterphenyl]-4-carbonyl)-3-(4-methylbenzyl)ureido)propanoic acid
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