|
|
| Line 3: |
Line 3: |
| | <StructureSection load='7jgv' size='340' side='right'caption='[[7jgv]], [[Resolution|resolution]] 2.05Å' scene=''> | | <StructureSection load='7jgv' size='340' side='right'caption='[[7jgv]], [[Resolution|resolution]] 2.05Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[7jgv]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7JGV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JGV FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[7jgv]] 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=7JGV OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7JGV FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V9S:6-[(8E)-8-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]hydrazinylidene}-5,6,7,8-tetrahydronaphthalen-2-yl]-3-(2-phenylethoxy)pyridine-2-carboxylic+acid'>V9S</scene></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]] 2.05Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">BCL2L1, BCL2L, BCLX ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=V9S:6-[(8E)-8-{2-[4-(benzylcarbamoyl)-1,3-thiazol-2-yl]hydrazinylidene}-5,6,7,8-tetrahydronaphthalen-2-yl]-3-(2-phenylethoxy)pyridine-2-carboxylic+acid'>V9S</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=7jgv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jgv OCA], [https://pdbe.org/7jgv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jgv RCSB], [https://www.ebi.ac.uk/pdbsum/7jgv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jgv ProSAT]</span></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=7jgv FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7jgv OCA], [https://pdbe.org/7jgv PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7jgv RCSB], [https://www.ebi.ac.uk/pdbsum/7jgv PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7jgv ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == 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>
| + | [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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
| Line 26: |
Line 26: |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Human]] | + | [[Category: Homo sapiens]] |
| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Fairlie, W D]] | + | [[Category: Fairlie WD]] |
| - | [[Category: Lee, E F]] | + | [[Category: Lee EF]] |
| - | [[Category: Lee, M]] | + | [[Category: Lee M]] |
| - | [[Category: Smith, B J]] | + | [[Category: Smith BJ]] |
| - | [[Category: Alternative splicing]]
| + | |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Membrane]]
| + | |
| - | [[Category: Mitochondrion]]
| + | |
| - | [[Category: Poptosis]]
| + | |
| 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]
Publication Abstract from PubMed
Limited therapeutic options are available for the treatment of human schistosomiasis caused by the parasitic Schistosoma flatworm. The B cell lymphoma-2 (BCL-2)-regulated apoptotic cell death pathway in schistosomes was recently characterized and shown to share similarities with the intrinsic apoptosis pathway in humans. Here, we exploit structural differences in the human and schistosome BCL-2 (sBCL-2) pro-survival proteins toward a novel treatment strategy for schistosomiasis. The benzothiazole hydrazone scaffold previously employed to target human BCL-XL was repurposed as a starting point to target sBCL-2. We utilized X-ray structural data to inform optimization and then applied a scaffold-hop strategy to identify the 5-carboxamide thiazole hydrazone scaffold (43) with potent sBCL-2 activity (IC50 30 nM). Human BCL-XL potency (IC50 13 nM) was inadvertently preserved during the optimization process. The lead analogues from this study exhibit on-target activity in model fibroblast cell lines dependent on either sBCL-2 or human BCL-XL for survival. Further optimization of the thiazole hydrazone class is required to exhibit activity in schistosomes and enhance the potential of this strategy for treating schistosomiasis.
Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2.,Nguyen W, Lee EF, Evangelista M, Lee M, Harris TJ, Colman PM, Smith NA, Williams LB, Jarman KE, Lowes KN, Haeberli C, Keiser J, Smith BJ, Fairlie WD, Sleebs BE ACS Infect Dis. 2021 Feb 1. doi: 10.1021/acsinfecdis.0c00700. PMID:33523649[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
- ↑ Nguyen W, Lee EF, Evangelista M, Lee M, Harris TJ, Colman PM, Smith NA, Williams LB, Jarman KE, Lowes KN, Haeberli C, Keiser J, Smith BJ, Fairlie WD, Sleebs BE. Optimization of Benzothiazole and Thiazole Hydrazones as Inhibitors of Schistosome BCL-2. ACS Infect Dis. 2021 Feb 1. doi: 10.1021/acsinfecdis.0c00700. PMID:33523649 doi:http://dx.doi.org/10.1021/acsinfecdis.0c00700
|
