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| | ==Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand== | | ==Solution structure of the anti-apoptotic protein Bcl-xL in complex with an acyl-sulfonamide-based ligand== |
| - | <StructureSection load='1ysi' size='340' side='right'caption='[[1ysi]], [[NMR_Ensembles_of_Models | 1 NMR models]]' scene=''> | + | <StructureSection load='1ysi' size='340' side='right'caption='[[1ysi]]' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1ysi]] is a 1 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1YSI OCA]. For a <b>guided tour on the structure components</b> use [http://proteopedia.org/fgij/fg.htm?mol=1YSI FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1ysi]] 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=1YSI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1YSI FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N3B:N-[(4-FLUORO-1,1-BIPHENYL-4-YL)CARBONYL]-3-NITRO-4-{[2-(PHENYLSULFANYL)ETHYL]AMINO}BENZENESULFONAMIDE'>N3B</scene></td></tr> | + | </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='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat"><div style='overflow: auto; max-height: 3em;'>[[1lxl|1lxl]], [[1maz|1maz]], [[1bxl|1bxl]], [[1g5j|1g5j]], [[1ysg|1ysg]], [[1ysx|1ysx]], [[1ysn|1ysn]], [[1ysw|1ysw]]</div></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=N3B:N-[(4-FLUORO-1,1-BIPHENYL-4-YL)CARBONYL]-3-NITRO-4-{[2-(PHENYLSULFANYL)ETHYL]AMINO}BENZENESULFONAMIDE'>N3B</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2L1, BCL2L, BCLX ([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'>[https://proteopedia.org/fgij/fg.htm?mol=1ysi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ysi OCA], [https://pdbe.org/1ysi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1ysi RCSB], [https://www.ebi.ac.uk/pdbsum/1ysi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1ysi ProSAT]</span></td></tr> |
| - | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://proteopedia.org/fgij/fg.htm?mol=1ysi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1ysi OCA], [http://pdbe.org/1ysi PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1ysi RCSB], [http://www.ebi.ac.uk/pdbsum/1ysi PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1ysi ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[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> | + | [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 == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Armstrong, R C]] | + | [[Category: Armstrong RC]] |
| - | [[Category: Augeri, D J]] | + | [[Category: Augeri DJ]] |
| - | [[Category: Belli, B A]] | + | [[Category: Belli BA]] |
| - | [[Category: Bruncko, M]] | + | [[Category: Bruncko M]] |
| - | [[Category: Connor, J M.O]]
| + | [[Category: Deckwerth TL]] |
| - | [[Category: Deckwerth, T L]] | + | [[Category: Dinges J]] |
| - | [[Category: Dinges, J]] | + | [[Category: Elmore SW]] |
| - | [[Category: Elmore, S W]] | + | [[Category: Fesik SW]] |
| - | [[Category: Fesik, S W]] | + | [[Category: Hajduk PJ]] |
| - | [[Category: Hajduk, P J]] | + | [[Category: Joseph MK]] |
| - | [[Category: Joseph, M K]] | + | [[Category: Kitada S]] |
| - | [[Category: Kitada, S]] | + | [[Category: Korsmeyer SJ]] |
| - | [[Category: Korsmeyer, S J]] | + | [[Category: Kunzer AR]] |
| - | [[Category: Kunzer, A R]] | + | [[Category: Letai A]] |
| - | [[Category: Letai, A]] | + | [[Category: Li C]] |
| - | [[Category: Li, C]] | + | [[Category: Mitten MJ]] |
| - | [[Category: Mitten, M J]] | + | [[Category: Nettesheim DG]] |
| - | [[Category: Nettesheim, D G]] | + | [[Category: Ng S]] |
| - | [[Category: Ng, S]] | + | [[Category: Nimmer PM]] |
| - | [[Category: Nimmer, P M]] | + | [[Category: O'Connor JM]] |
| - | [[Category: Oleksijew, A]] | + | [[Category: Oleksijew A]] |
| - | [[Category: Oltersdorf, T]] | + | [[Category: Oltersdorf T]] |
| - | [[Category: Petros, A M]] | + | [[Category: Petros AM]] |
| - | [[Category: Reed, J C]] | + | [[Category: Reed JC]] |
| - | [[Category: Rosenberg, S H]] | + | [[Category: Rosenberg SH]] |
| - | [[Category: Shen, W]] | + | [[Category: Shen W]] |
| - | [[Category: Shoemaker, A R]] | + | [[Category: Shoemaker AR]] |
| - | [[Category: Tahir, S K]] | + | [[Category: Tahir SK]] |
| - | [[Category: Thompson, C B]] | + | [[Category: Thompson CB]] |
| - | [[Category: Tomaselli, K J]] | + | [[Category: Tomaselli KJ]] |
| - | [[Category: Wang, B]] | + | [[Category: Wang B]] |
| - | [[Category: Wendt, M D]] | + | [[Category: Wendt MD]] |
| - | [[Category: Zhang, H]] | + | [[Category: Zhang H]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Complex]]
| + | |
| Structural highlights
Function
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.[1] [2] Isoform Bcl-X(S) promotes apoptosis.[3] [4]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Proteins in the Bcl-2 family are central regulators of programmed cell death, and members that inhibit apoptosis, such as Bcl-X(L) and Bcl-2, are overexpressed in many cancers and contribute to tumour initiation, progression and resistance to therapy. Bcl-X(L) expression correlates with chemo-resistance of tumour cell lines, and reductions in Bcl-2 increase sensitivity to anticancer drugs and enhance in vivo survival. The development of inhibitors of these proteins as potential anti-cancer therapeutics has been previously explored, but obtaining potent small-molecule inhibitors has proved difficult owing to the necessity of targeting a protein-protein interaction. Here, using nuclear magnetic resonance (NMR)-based screening, parallel synthesis and structure-based design, we have discovered ABT-737, a small-molecule inhibitor of the anti-apoptotic proteins Bcl-2, Bcl-X(L) and Bcl-w, with an affinity two to three orders of magnitude more potent than previously reported compounds. Mechanistic studies reveal that ABT-737 does not directly initiate the apoptotic process, but enhances the effects of death signals, displaying synergistic cytotoxicity with chemotherapeutics and radiation. ABT-737 exhibits single-agent-mechanism-based killing of cells from lymphoma and small-cell lung carcinoma lines, as well as primary patient-derived cells, and in animal models, ABT-737 improves survival, causes regression of established tumours, and produces cures in a high percentage of the mice.
An inhibitor of Bcl-2 family proteins induces regression of solid tumours.,Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH Nature. 2005 Jun 2;435(7042):677-81. Epub 2005 May 15. PMID:15902208[5]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
- ↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
- ↑ Terrano DT, Upreti M, Chambers TC. Cyclin-dependent kinase 1-mediated Bcl-xL/Bcl-2 phosphorylation acts as a functional link coupling mitotic arrest and apoptosis. Mol Cell Biol. 2010 Feb;30(3):640-56. doi: 10.1128/MCB.00882-09. Epub 2009 Nov, 16. PMID:19917720 doi:10.1128/MCB.00882-09
- ↑ Wang J, Beauchemin M, Bertrand R. Bcl-xL phosphorylation at Ser49 by polo kinase 3 during cell cycle progression and checkpoints. Cell Signal. 2011 Dec;23(12):2030-8. doi: 10.1016/j.cellsig.2011.07.017. Epub, 2011 Aug 5. PMID:21840391 doi:10.1016/j.cellsig.2011.07.017
- ↑ Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, Bruncko M, Deckwerth TL, Dinges J, Hajduk PJ, Joseph MK, Kitada S, Korsmeyer SJ, Kunzer AR, Letai A, Li C, Mitten MJ, Nettesheim DG, Ng S, Nimmer PM, O'Connor JM, Oleksijew A, Petros AM, Reed JC, Shen W, Tahir SK, Thompson CB, Tomaselli KJ, Wang B, Wendt MD, Zhang H, Fesik SW, Rosenberg SH. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature. 2005 Jun 2;435(7042):677-81. Epub 2005 May 15. PMID:15902208 doi:10.1038/nature03579
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