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| | ==Tailoring Small Molecules for an Allosteric Site on Procaspase-6: Cpd1== | | ==Tailoring Small Molecules for an Allosteric Site on Procaspase-6: Cpd1== |
| - | <StructureSection load='4n5d' size='340' side='right' caption='[[4n5d]], [[Resolution|resolution]] 2.06Å' scene=''> | + | <StructureSection load='4n5d' size='340' side='right'caption='[[4n5d]], [[Resolution|resolution]] 2.06Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4n5d]] 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=4N5D OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4N5D FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4n5d]] 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=4N5D OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4N5D FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=2FQ:6-AMINO-2,8-DIMETHYLPYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>2FQ</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</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]] 2.06Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4n6g|4n6g]], [[4n7j|4n7j]], [[4n7m|4n7m]], [[4nbk|4nbk]], [[4nbl|4nbl]], [[4nbn|4nbn]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=2FQ:6-AMINO-2,8-DIMETHYLPYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE'>2FQ</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASP6, MCH2, procaspase-6 ([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=4n5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n5d OCA], [https://pdbe.org/4n5d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4n5d RCSB], [https://www.ebi.ac.uk/pdbsum/4n5d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4n5d ProSAT]</span></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Caspase-6 Caspase-6], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.59 3.4.22.59] </span></td></tr>
| + | |
| - | <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=4n5d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4n5d OCA], [http://pdbe.org/4n5d PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4n5d RCSB], [http://www.ebi.ac.uk/pdbsum/4n5d PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4n5d ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CASP6_HUMAN CASP6_HUMAN]] Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. | + | [https://www.uniprot.org/uniprot/CASP6_HUMAN CASP6_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. Cleaves poly(ADP-ribose) polymerase in vitro, as well as lamins. Overexpression promotes programmed cell death. |
| - | <div style="background-color:#fffaf0;">
| + | |
| - | == Publication Abstract from PubMed ==
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| - | Although they represent attractive therapeutic targets, caspases have so far proven recalcitrant to the development of drugs targeting the active site. Allosteric modulation of caspase activity is an alternate strategy that potentially avoids the need for anionic and electrophilic functionality present in most active-site inhibitors. Caspase-6 has been implicated in neurodegenerative disease, including Huntington's and Alzheimer's diseases. Herein we describe a fragment-based lead discovery effort focused on caspase-6 in its active and zymogen forms. Fragments were identified for procaspase-6 using surface plasmon resonance methods and subsequently shown by X-ray crystallography to bind a putative allosteric site at the dimer interface. A fragment-merging strategy was employed to produce nanomolar-affinity ligands that contact residues in the L2 loop at the dimer interface, significantly stabilizing procaspase-6. Because rearrangement of the L2 loop is required for caspase-6 activation, our results suggest a strategy for the allosteric control of caspase activation with drug-like small molecules.
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| - | | + | |
| - | Tailoring Small Molecules for an Allosteric Site on Procaspase-6.,Murray J, Giannetti AM, Steffek M, Gibbons P, Hearn BR, Cohen F, Tam C, Pozniak C, Bravo B, Lewcock J, Jaishankar P, Ly CQ, Zhao X, Tang Y, Chugha P, Arkin MR, Flygare J, Renslo AR ChemMedChem. 2013 Nov 20. doi: 10.1002/cmdc.201300424. PMID:24259468<ref>PMID:24259468</ref>
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| - | | + | |
| - | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>
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| - | </div>
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| - | <div class="pdbe-citations 4n5d" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Caspase|Caspase]] | + | *[[Caspase 3D structures|Caspase 3D structures]] |
| - | == References ==
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| - | <references/>
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Caspase-6]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Murray, J M]] | + | [[Category: Murray JM]] |
| - | [[Category: Steffek, M]] | + | [[Category: Steffek M]] |
| - | [[Category: Allosteric]]
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| - | [[Category: Caspase-6 zymogen]]
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| - | [[Category: Cysteine protease]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| - | [[Category: Procaspse-6]]
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| - | [[Category: Structure based drug design]]
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