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| | ==Caspase 8 bound to a covalent inhibitor== | | ==Caspase 8 bound to a covalent inhibitor== |
| - | <StructureSection load='3kjn' size='340' side='right' caption='[[3kjn]], [[Resolution|resolution]] 1.80Å' scene=''> | + | <StructureSection load='3kjn' size='340' side='right'caption='[[3kjn]], [[Resolution|resolution]] 1.80Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[3kjn]] 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=3KJN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=3KJN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[3kjn]] 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=3KJN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3KJN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=B93:(3S)-3-({[(5S)-2-{2-[(1H-BENZIMIDAZOL-5-YLCARBONYL)AMINO]ETHYL}-7-(CYCLOHEXYLMETHYL)-1,3-DIOXO-2,3,5,8-TETRAHYDRO-1H-[1,2,4]TRIAZOLO[1,2-A]PYRIDAZIN-5-YL]CARBONYL}AMINO)-4-OXOPENTANOIC+ACID'>B93</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</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]] 1.8Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[3kjf|3kjf]], [[3kjq|3kjq]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=B93:(3S)-3-({[(5S)-2-{2-[(1H-BENZIMIDAZOL-5-YLCARBONYL)AMINO]ETHYL}-7-(CYCLOHEXYLMETHYL)-1,3-DIOXO-2,3,5,8-TETRAHYDRO-1H-[1,2,4]TRIAZOLO[1,2-A]PYRIDAZIN-5-YL]CARBONYL}AMINO)-4-OXOPENTANOIC+ACID'>B93</scene>, <scene name='pdbligand=DTT:2,3-DIHYDROXY-1,4-DITHIOBUTANE'>DTT</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASP8, MCH5 ([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=3kjn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kjn OCA], [https://pdbe.org/3kjn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3kjn RCSB], [https://www.ebi.ac.uk/pdbsum/3kjn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3kjn 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-8 Caspase-8], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.61 3.4.22.61] </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=3kjn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3kjn OCA], [http://pdbe.org/3kjn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=3kjn RCSB], [http://www.ebi.ac.uk/pdbsum/3kjn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=3kjn ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Disease == | | == Disease == |
| - | [[http://www.uniprot.org/uniprot/CASP8_HUMAN CASP8_HUMAN]] Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:[http://omim.org/entry/607271 607271]]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.<ref>PMID:12353035</ref> | + | [https://www.uniprot.org/uniprot/CASP8_HUMAN CASP8_HUMAN] Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:[https://omim.org/entry/607271 607271]. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.<ref>PMID:12353035</ref> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CASP8_HUMAN CASP8_HUMAN]] Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.<ref>PMID:12010809</ref> <ref>PMID:9006941</ref> | + | [https://www.uniprot.org/uniprot/CASP8_HUMAN CASP8_HUMAN] Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.<ref>PMID:12010809</ref> <ref>PMID:9006941</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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| | <jmolCheckbox> | | <jmolCheckbox> |
| | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kj/3kjn_consurf.spt"</scriptWhenChecked> | | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/kj/3kjn_consurf.spt"</scriptWhenChecked> |
| - | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview03.spt</scriptWhenUnchecked> |
| | <text>to colour the structure by Evolutionary Conservation</text> | | <text>to colour the structure by Evolutionary Conservation</text> |
| | </jmolCheckbox> | | </jmolCheckbox> |
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| | ==See Also== | | ==See Also== |
| - | *[[Caspase|Caspase]] | + | *[[Caspase 3D structures|Caspase 3D structures]] |
| | == References == | | == References == |
| | <references/> | | <references/> |
| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Caspase-8]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Blinn, J]] | + | [[Category: Blinn J]] |
| - | [[Category: Finzel, B C]] | + | [[Category: Finzel BC]] |
| - | [[Category: Harris, M S]] | + | [[Category: Harris MS]] |
| - | [[Category: Kamtekar, S]] | + | [[Category: Kamtekar S]] |
| - | [[Category: Tomasselli, A G]] | + | [[Category: Tomasselli AG]] |
| - | [[Category: Wang, Z]] | + | [[Category: Wang Z]] |
| - | [[Category: Watt, W]] | + | [[Category: Watt W]] |
| - | [[Category: Caspase 8]]
| + | |
| - | [[Category: Hydrolase-hydrolase inhibitor complex]]
| + | |
| - | [[Category: Kinetic]]
| + | |
| - | [[Category: Peptidomimetic inhibitor]]
| + | |
| - | [[Category: Thiol protease]]
| + | |
| - | [[Category: Urazole]]
| + | |
| - | [[Category: Zymogen]]
| + | |
| Structural highlights
Disease
CASP8_HUMAN Defects in CASP8 are the cause of caspase-8 deficiency (CASP8D) [MIM:607271. CASP8D is a disorder resembling autoimmune lymphoproliferative syndrome (ALPS). It is characterized by lymphadenopathy, splenomegaly, and defective CD95-induced apoptosis of peripheral blood lymphocytes (PBLs). It leads to defects in activation of T-lymphocytes, B-lymphocytes, and natural killer cells leading to immunodeficiency characterized by recurrent sinopulmonary and herpes simplex virus infections and poor responses to immunization.[1]
Function
CASP8_HUMAN Most upstream protease of the activation cascade of caspases responsible for the TNFRSF6/FAS mediated and TNFRSF1A induced cell death. Binding to the adapter molecule FADD recruits it to either receptor. The resulting aggregate called death-inducing signaling complex (DISC) performs CASP8 proteolytic activation. The active dimeric enzyme is then liberated from the DISC and free to activate downstream apoptotic proteases. Proteolytic fragments of the N-terminal propeptide (termed CAP3, CAP5 and CAP6) are likely retained in the DISC. Cleaves and activates CASP3, CASP4, CASP6, CASP7, CASP9 and CASP10. May participate in the GZMB apoptotic pathways. Cleaves ADPRT. Hydrolyzes the small-molecule substrate, Ac-Asp-Glu-Val-Asp-|-AMC. Likely target for the cowpox virus CRMA death inhibitory protein. Isoform 5, isoform 6, isoform 7 and isoform 8 lack the catalytic site and may interfere with the pro-apoptotic activity of the complex.[2] [3]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
Because of their central role in programmed cell death, the caspases are attractive targets for developing new therapeutics against cancer and autoimmunity, myocardial infarction and ischemic damage, and neurodegenerative diseases. We chose to target caspase-3, an executioner caspase, and caspase-8, an initiator caspase, based on the vast amount of information linking their functions to diseases. Through a structure-based drug design approach, a number of novel beta-strand peptidomimetic compounds were synthesized. Kinetic studies of caspase-3 and caspase-8 inhibition were carried out with these urazole ring-containing irreversible peptidomimetics and a known irreversible caspase inhibitor, Z-VAD-fmk. Using a stopped-flow fluorescence assay, we were able to determine individual kinetic parameters of caspase-3 and caspase-8 inhibition by these inhibitors. Z-VAD-fmk and the peptidomimetic inhibitors inhibit caspase-3 and caspase-8 via a three-step kinetic mechanism. Inhibition of both caspase-3 and caspase-8 by Z-VAD-fmk and of caspase-3 by the peptidomimetic inhibitors proceeds via two rapid equilibrium steps followed by a relatively fast inactivation step. However, caspase-8 inhibition by the peptidomimetics goes through a rapid equilibrium step, a slow-binding reversible step, and an extremely slow inactivation step. The crystal structures of inhibitor complexes of caspases-3 and -8 validate the design of the inhibitors by illustrating in detail how they mimic peptide substrates. One of the caspase-8 structures also shows binding at a secondary, allosteric site, providing a possible route to the development of noncovalent small molecule modulators of caspase activity.
Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors.,Wang Z, Watt W, Brooks NA, Harris MS, Urban J, Boatman D, McMillan M, Kahn M, Heinrikson RL, Finzel BC, Wittwer AJ, Blinn J, Kamtekar S, Tomasselli AG Biochim Biophys Acta. 2010 Sep;1804(9):1817-1831. Epub 2010 May 24. PMID:20580860[4]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chun HJ, Zheng L, Ahmad M, Wang J, Speirs CK, Siegel RM, Dale JK, Puck J, Davis J, Hall CG, Skoda-Smith S, Atkinson TP, Straus SE, Lenardo MJ. Pleiotropic defects in lymphocyte activation caused by caspase-8 mutations lead to human immunodeficiency. Nature. 2002 Sep 26;419(6905):395-9. PMID:12353035 doi:10.1038/nature01063
- ↑ Himeji D, Horiuchi T, Tsukamoto H, Hayashi K, Watanabe T, Harada M. Characterization of caspase-8L: a novel isoform of caspase-8 that behaves as an inhibitor of the caspase cascade. Blood. 2002 Jun 1;99(11):4070-8. PMID:12010809
- ↑ Muzio M, Salvesen GS, Dixit VM. FLICE induced apoptosis in a cell-free system. Cleavage of caspase zymogens. J Biol Chem. 1997 Jan 31;272(5):2952-6. PMID:9006941
- ↑ Wang Z, Watt W, Brooks NA, Harris MS, Urban J, Boatman D, McMillan M, Kahn M, Heinrikson RL, Finzel BC, Wittwer AJ, Blinn J, Kamtekar S, Tomasselli AG. Kinetic and structural characterization of caspase-3 and caspase-8 inhibition by a novel class of irreversible inhibitors. Biochim Biophys Acta. 2010 Sep;1804(9):1817-1831. Epub 2010 May 24. PMID:20580860 doi:10.1016/j.bbapap.2010.05.007
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