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| | <StructureSection load='3rjm' size='340' side='right'caption='[[3rjm]], [[Resolution|resolution]] 2.55Å' scene=''> | | <StructureSection load='3rjm' size='340' side='right'caption='[[3rjm]], [[Resolution|resolution]] 2.55Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3rjm]] is a 6 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=3RJM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RJM FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3rjm]] is a 6 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=3RJM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3RJM FirstGlance]. <br> |
| - | </td></tr><tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=3PX:(3S)-3-(PROPAN-2-YLOXY)-L-PROLINE'>3PX</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=ASJ:(3S)-3-AMINO-4-HYDROXYBUTANOIC+ACID'>ASJ</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]] 2.55Å</td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASP2, Caspase-2, ICH1, NEDD2, p19 ([https://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN]), CASP2, Caspase-2, ICH1, NEDD2, p12 ([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=3PX:(3S)-3-(PROPAN-2-YLOXY)-L-PROLINE'>3PX</scene>, <scene name='pdbligand=ACE:ACETYL+GROUP'>ACE</scene>, <scene name='pdbligand=ASJ:(3S)-3-AMINO-4-HYDROXYBUTANOIC+ACID'>ASJ</scene></td></tr> |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Caspase-2 Caspase-2], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.55 3.4.22.55] </span></td></tr>
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| | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3rjm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rjm OCA], [https://pdbe.org/3rjm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rjm RCSB], [https://www.ebi.ac.uk/pdbsum/3rjm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rjm 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=3rjm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3rjm OCA], [https://pdbe.org/3rjm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3rjm RCSB], [https://www.ebi.ac.uk/pdbsum/3rjm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3rjm ProSAT]</span></td></tr> |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[https://www.uniprot.org/uniprot/CASP2_HUMAN CASP2_HUMAN]] Involved in the activation cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival.
| + | [https://www.uniprot.org/uniprot/CASP2_HUMAN CASP2_HUMAN] Involved in the activation cascade of caspases responsible for apoptosis execution. Might function by either activating some proteins required for cell death or inactivating proteins necessary for cell survival. |
| - | <div style="background-color:#fffaf0;">
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| - | == Publication Abstract from PubMed ==
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| - | Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P(2) residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-l-proline along with four additional scaffold variants were selected as P(2) elements for their predicted ability to clash sterically with a residue of the caspase-3 S(2) pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and approximately 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD.
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| - | Exploiting differences in caspase-2 and -3 S(2) subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors.,Maillard MC, Brookfield FA, Courtney SM, Eustache FM, Gemkow MJ, Handel RK, Johnson LC, Johnson PD, Kerry MA, Krieger F, Meniconi M, Munoz-Sanjuan I, Palfrey JJ, Park H, Schaertl S, Taylor MG, Weddell D, Dominguez C Bioorg Med Chem. 2011 Oct 1;19(19):5833-51. Epub 2011 Aug 16. PMID:21903398<ref>PMID:21903398</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 3rjm" style="background-color:#fffaf0;"></div>
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| | | | |
| | ==See Also== | | ==See Also== |
| | *[[Caspase 3D structures|Caspase 3D structures]] | | *[[Caspase 3D structures|Caspase 3D structures]] |
| - | == References == | |
| - | <references/> | |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Caspase-2]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]]
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| | [[Category: Large Structures]] | | [[Category: Large Structures]] |
| - | [[Category: Abendroth, J]] | + | [[Category: Abendroth J]] |
| - | [[Category: Kiselyov, A S]] | + | [[Category: Kiselyov AS]] |
| - | [[Category: Lorimer, D]] | + | [[Category: Lorimer D]] |
| - | [[Category: Maillard, M]] | + | [[Category: Maillard M]] |
| - | [[Category: Stewart, L]] | + | [[Category: Stewart L]] |
| - | [[Category: Caspase]]
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| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
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| - | [[Category: P12]]
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| - | [[Category: P19]]
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