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| | ==Caspase-3 in Complex with an Inhibitory DARPin-3.4_S76R== | | ==Caspase-3 in Complex with an Inhibitory DARPin-3.4_S76R== |
| - | <StructureSection load='2y0b' size='340' side='right' caption='[[2y0b]], [[Resolution|resolution]] 2.10Å' scene=''> | + | <StructureSection load='2y0b' size='340' side='right'caption='[[2y0b]], [[Resolution|resolution]] 2.10Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[2y0b]] is a 6 chain structure with sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [http://en.wikipedia.org/wiki/Unidentified Unidentified]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y0B OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=2Y0B FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[2y0b]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] and [https://en.wikipedia.org/wiki/Synthetic_construct Synthetic construct]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2Y0B OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2Y0B FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</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]] 2.1Å</td></tr> |
| - | <tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene></td></tr> | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CSO:S-HYDROXYCYSTEINE'>CSO</scene>, <scene name='pdbligand=MPD:(4S)-2-METHYL-2,4-PENTANEDIOL'>MPD</scene>, <scene name='pdbligand=MRD:(4R)-2-METHYLPENTANE-2,4-DIOL'>MRD</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[2xzd|2xzd]], [[1rhk|1rhk]], [[1rhq|1rhq]], [[2dko|2dko]], [[2xyp|2xyp]], [[2j31|2j31]], [[2cjy|2cjy]], [[2xyh|2xyh]], [[2cjx|2cjx]], [[1re1|1re1]], [[2xyg|2xyg]], [[2c1e|2c1e]], [[2cno|2cno]], [[1gfw|1gfw]], [[1qx3|1qx3]], [[1rhm|1rhm]], [[1nme|1nme]], [[2j33|2j33]], [[1rhr|1rhr]], [[1nms|1nms]], [[1nmq|1nmq]], [[1rhj|1rhj]], [[2cnn|2cnn]], [[2c2k|2c2k]], [[2cnl|2cnl]], [[2c2m|2c2m]], [[1cp3|1cp3]], [[2cnk|2cnk]], [[2j30|2j30]], [[1pau|1pau]], [[2xzt|2xzt]], [[2cdr|2cdr]], [[1i3o|1i3o]], [[2j32|2j32]], [[1rhu|1rhu]], [[2c2o|2c2o]]</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=2y0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y0b OCA], [https://pdbe.org/2y0b PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2y0b RCSB], [https://www.ebi.ac.uk/pdbsum/2y0b PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2y0b 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-3 Caspase-3], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.56 3.4.22.56] </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=2y0b FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2y0b OCA], [http://www.rcsb.org/pdb/explore.do?structureId=2y0b RCSB], [http://www.ebi.ac.uk/pdbsum/2y0b PDBsum]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CASP3_HUMAN CASP3_HUMAN]] Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage.<ref>PMID:7596430</ref> <ref>PMID:21357690</ref> | + | [https://www.uniprot.org/uniprot/CASP3_HUMAN CASP3_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage.<ref>PMID:7596430</ref> <ref>PMID:21357690</ref> |
| | <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 2y0b" 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-3]] | |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Unidentified]] | + | [[Category: Large Structures]] |
| - | [[Category: Barandun, J]] | + | [[Category: Synthetic construct]] |
| - | [[Category: Grutter, M G]] | + | [[Category: Barandun J]] |
| - | [[Category: Mittl, P]] | + | [[Category: Grutter MG]] |
| - | [[Category: Schroeder, T]] | + | [[Category: Mittl P]] |
| - | [[Category: Ankyrin repeat protein]]
| + | [[Category: Schroeder T]] |
| - | [[Category: Apoptosis]]
| + | |
| - | [[Category: Hydrolase-protein binding complex]]
| + | |
| - | [[Category: Ribosome display]]
| + | |
| - | [[Category: Structure-activity relationship]]
| + | |
| Structural highlights
Function
CASP3_HUMAN Involved in the activation cascade of caspases responsible for apoptosis execution. At the onset of apoptosis it proteolytically cleaves poly(ADP-ribose) polymerase (PARP) at a '216-Asp-|-Gly-217' bond. Cleaves and activates sterol regulatory element binding proteins (SREBPs) between the basic helix-loop-helix leucine zipper domain and the membrane attachment domain. Cleaves and activates caspase-6, -7 and -9. Involved in the cleavage of huntingtin. Triggers cell adhesion in sympathetic neurons through RET cleavage.[1] [2]
Publication Abstract from PubMed
Dysregulation of apoptosis is associated with several human diseases. The main apoptotic mediators are caspases, which propagate death signals to downstream targets. Executioner caspase-3 is responsible for the majority of cleavage events and its therapeutic potential is of high interest with to date several available active site peptide inhibitors. These molecules inhibit caspase-3, but also homologous caspases. Here, we describe caspase-3 specific inhibitors D3.4 and D3.8, which have been selected from a library of designed ankyrin repeat proteins (DARPins). The crystal structures of D3.4 and mutants thereof show how high specificity and inhibition is achieved. They also show similarities in the binding mode with that of the natural caspase inhibitor XIAP (X-linked inhibitor of apoptosis). The kinetic data reveal a competitive inhibition mechanism. D3.4 is specific for caspase-3 and does not bind the highly homologous caspase-7. D3.4 therefore is an excellent tool to define the precise role of caspase-3 in the various apoptotic pathways.
Specific Inhibition of Caspase-3 by a Competitive DARPin: Molecular Mimicry between Native and Designed Inhibitors.,Schroeder T, Barandun J, Flutsch A, Briand C, Mittl PR, Grutter MG Structure. 2013 Jan 15. pii: S0969-2126(12)00466-2. doi:, 10.1016/j.str.2012.12.011. PMID:23333429[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Nicholson DW, Ali A, Thornberry NA, Vaillancourt JP, Ding CK, Gallant M, Gareau Y, Griffin PR, Labelle M, Lazebnik YA, et al.. Identification and inhibition of the ICE/CED-3 protease necessary for mammalian apoptosis. Nature. 1995 Jul 6;376(6535):37-43. PMID:7596430 doi:http://dx.doi.org/10.1038/376037a0
- ↑ Cabrera JR, Bouzas-Rodriguez J, Tauszig-Delamasure S, Mehlen P. RET modulates cell adhesion via its cleavage by caspase in sympathetic neurons. J Biol Chem. 2011 Apr 22;286(16):14628-38. doi: 10.1074/jbc.M110.195461. Epub, 2011 Feb 28. PMID:21357690 doi:10.1074/jbc.M110.195461
- ↑ Schroeder T, Barandun J, Flutsch A, Briand C, Mittl PR, Grutter MG. Specific Inhibition of Caspase-3 by a Competitive DARPin: Molecular Mimicry between Native and Designed Inhibitors. Structure. 2013 Jan 15. pii: S0969-2126(12)00466-2. doi:, 10.1016/j.str.2012.12.011. PMID:23333429 doi:http://dx.doi.org/10.1016/j.str.2012.12.011
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