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| | ==Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6== | | ==Mechanistic and Structural Understanding of Uncompetitive Inhibitors of Caspase-6== |
| - | <StructureSection load='4hva' size='340' side='right' caption='[[4hva]], [[Resolution|resolution]] 2.07Å' scene=''> | + | <StructureSection load='4hva' size='340' side='right'caption='[[4hva]], [[Resolution|resolution]] 2.07Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4hva]] is a 4 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4HVA OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4HVA FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4hva]] is a 4 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=4HVA OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4HVA FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4HV:N-[(2R)-1-(3-CYANOPHENYL)-3-HYDROXYPROPAN-2-YL]-5-(3,4-DIMETHOXYPHENYL)FURAN-3-CARBOXAMIDE'>4HV</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]] 2.074Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=4H0:(3S)-3-AMINO-4-OXO-5-(2,3,5,6-TETRAFLUOROPHENOXY)PENTANOIC+ACID'>4H0</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4H0:(3S)-3-AMINO-4-OXO-5-(2,3,5,6-TETRAFLUOROPHENOXY)PENTANOIC+ACID'>4H0</scene>, <scene name='pdbligand=4HV:N-[(2R)-1-(3-CYANOPHENYL)-3-HYDROXYPROPAN-2-YL]-5-(3,4-DIMETHOXYPHENYL)FURAN-3-CARBOXAMIDE'>4HV</scene>, <scene name='pdbligand=PHQ:BENZYL+CHLOROCARBONATE'>PHQ</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASP6, MCH2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 Homo sapiens])</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=4hva FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hva OCA], [https://pdbe.org/4hva PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4hva RCSB], [https://www.ebi.ac.uk/pdbsum/4hva PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4hva 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=4hva FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4hva OCA], [http://www.rcsb.org/pdb/explore.do?structureId=4hva RCSB], [http://www.ebi.ac.uk/pdbsum/4hva PDBsum]</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;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| | </div> | | </div> |
| | + | <div class="pdbe-citations 4hva" style="background-color:#fffaf0;"></div> |
| | | | |
| | ==See Also== | | ==See Also== |
| - | *[[Caspase|Caspase]] | + | *[[Caspase 3D structures|Caspase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Caspase-6]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Murray, J M]] | + | [[Category: Large Structures]] |
| - | [[Category: Steffek, M]] | + | [[Category: Murray JM]] |
| - | [[Category: Active]] | + | [[Category: Steffek M]] |
| - | [[Category: Caspase]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Protease]]
| + | |
| - | [[Category: Ternary complex]]
| + | |
| - | [[Category: Uncompetitive inhibition]]
| + | |
| - | [[Category: Veid]]
| + | |
| Structural highlights
Function
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.
Publication Abstract from PubMed
Inhibition of caspase-6 is a potential therapeutic strategy for some neurodegenerative diseases, but it has been difficult to develop selective inhibitors against caspases. We report the discovery and characterization of a potent inhibitor of caspase-6 that acts by an uncompetitive binding mode that is an unprecedented mechanism of inhibition against this target class. Biochemical assays demonstrate that, while exquisitely selective for caspase-6 over caspase-3 and -7, the compound's inhibitory activity is also dependent on the amino acid sequence and P1' character of the peptide substrate. The crystal structure of the ternary complex of caspase-6, substrate-mimetic and an 11 nM inhibitor reveals the molecular basis of inhibition. The general strategy to develop uncompetitive inhibitors together with the unique mechanism described herein provides a rationale for engineering caspase selectivity.
Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6.,Heise CE, Murray J, Augustyn KE, Bravo B, Chugha P, Cohen F, Giannetti AM, Gibbons P, Hannoush RN, Hearn BR, Jaishankar P, Ly CQ, Shah K, Stanger K, Steffek M, Tang Y, Zhao X, Lewcock JW, Renslo AR, Flygare J, Arkin MR PLoS One. 2012;7(12):e50864. doi: 10.1371/journal.pone.0050864. Epub 2012 Dec 5. PMID:23227217[1]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Heise CE, Murray J, Augustyn KE, Bravo B, Chugha P, Cohen F, Giannetti AM, Gibbons P, Hannoush RN, Hearn BR, Jaishankar P, Ly CQ, Shah K, Stanger K, Steffek M, Tang Y, Zhao X, Lewcock JW, Renslo AR, Flygare J, Arkin MR. Mechanistic and structural understanding of uncompetitive inhibitors of caspase-6. PLoS One. 2012;7(12):e50864. doi: 10.1371/journal.pone.0050864. Epub 2012 Dec 5. PMID:23227217 doi:http://dx.doi.org/10.1371/journal.pone.0050864
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