2o1y: Difference between revisions
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== | ==Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand== | ||
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a | <StructureSection load='2o1y' size='340' side='right'caption='[[2o1y]]' scene=''> | ||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[2o1y]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2O1Y OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2O1Y FirstGlance]. <br> | |||
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=43B:3-NITRO-N-{4-[2-(2-PHENYLETHYL)-1,3-BENZOTHIAZOL-5-YL]BENZOYL}-4-{[2-(PHENYLSULFANYL)ETHYL]AMINO}BENZENESULFONAMIDE'>43B</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=2o1y FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2o1y OCA], [https://pdbe.org/2o1y PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2o1y RCSB], [https://www.ebi.ac.uk/pdbsum/2o1y PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2o1y ProSAT]</span></td></tr> | |||
</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> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/o1/2o1y_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2o1y ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Overexpression of the antiapototic proteins Bcl-2 and Bcl-xL provides a common mechanism through which cancer cells gain a survival advantage and become resistant to conventional chemotherapy. Inhibition of these prosurvival proteins is an attractive strategy for cancer therapy. We recently described the discovery of a selective Bcl-xL antagonist that potentiates the antitumor activity of chemotherapy and radiation. Here we describe the use of structure-guided design to exploit a deep hydrophobic binding pocket on the surface of these proteins to develop the first dual, subnanomolar inhibitors of Bcl-xL and Bcl-2. This study culminated in the identification of 2, which exhibited EC50 values of 8 nM and 30 nM in Bcl-2 and Bcl-xL dependent cells, respectively. Compound 2 demonstrated single agent efficacy against human follicular lymphoma cell lines that overexpress Bcl-2, and efficacy in a murine xenograft model of lymphoma when given both as a single agent and in combination with etoposide. | |||
Studies leading to potent, dual inhibitors of Bcl-2 and Bcl-xL.,Bruncko M, Oost TK, Belli BA, Ding H, Joseph MK, Kunzer A, Martineau D, McClellan WJ, Mitten M, Ng SC, Nimmer PM, Oltersdorf T, Park CM, Petros AM, Shoemaker AR, Song X, Wang X, Wendt MD, Zhang H, Fesik SW, Rosenberg SH, Elmore SW J Med Chem. 2007 Feb 22;50(4):641-62. Epub 2007 Jan 26. PMID:17256834<ref>PMID:17256834</ref> | |||
== | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
</div> | |||
<div class="pdbe-citations 2o1y" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[B-cell lymphoma proteins 3D structures|B-cell lymphoma proteins 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: Belli | [[Category: Belli BA]] | ||
[[Category: Bruncko | [[Category: Bruncko M]] | ||
[[Category: Ding | [[Category: Ding H]] | ||
[[Category: Elmore | [[Category: Elmore SW]] | ||
[[Category: Fesik | [[Category: Fesik SW]] | ||
[[Category: Joseph | [[Category: Joseph MK]] | ||
[[Category: Kunzer | [[Category: Kunzer A]] | ||
[[Category: Martineau | [[Category: Martineau D]] | ||
[[Category: McClellan | [[Category: McClellan WJ]] | ||
[[Category: Mitten | [[Category: Mitten M]] | ||
[[Category: Ng | [[Category: Ng SC]] | ||
[[Category: Nimmer | [[Category: Nimmer PM]] | ||
[[Category: Oltersdorf | [[Category: Oltersdorf T]] | ||
[[Category: Oost | [[Category: Oost TK]] | ||
[[Category: Park | [[Category: Park CM]] | ||
[[Category: Petros | [[Category: Petros AM]] | ||
[[Category: Rosenberg | [[Category: Rosenberg SH]] | ||
[[Category: Shoemaker | [[Category: Shoemaker AR]] | ||
[[Category: Song | [[Category: Song X]] | ||
[[Category: Wang | [[Category: Wang X]] | ||
[[Category: Wendt | [[Category: Wendt MD]] | ||
[[Category: Zhang | [[Category: Zhang H]] | ||
