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| | ==Crystal structure of human caspase-1 in complex with 3-{2-ethyl-6-[4-(quinoxalin-2-ylamino)-benzoylamino]-hexanoylamino}-4-oxo-butyric acid== | | ==Crystal structure of human caspase-1 in complex with 3-{2-ethyl-6-[4-(quinoxalin-2-ylamino)-benzoylamino]-hexanoylamino}-4-oxo-butyric acid== |
| - | <StructureSection load='1rwn' size='340' side='right' caption='[[1rwn]], [[Resolution|resolution]] 2.00Å' scene=''> | + | <StructureSection load='1rwn' size='340' side='right'caption='[[1rwn]], [[Resolution|resolution]] 2.00Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[1rwn]] 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=1RWN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=1RWN FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[1rwn]] 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=1RWN OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RWN FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=4QB:3-{2-ETHYL-6-[4-(QUINOXALIN-2-YLAMINO)-BENZOYLAMINO]-HEXANOYLAMINO}-4-OXO-BUTYRIC+ACID'>4QB</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]] 2Å</td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[1ice|1ice]], [[1bmq|1bmq]], [[1ibc|1ibc]], [[1rwk|1rwk]], [[1rwm|1rwm]], [[1rwo|1rwo]], [[1rwp|1rwp]], [[1rwv|1rwv]], [[1rww|1rww]], [[1rwx|1rwx]]</td></tr>
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=4QB:3-{2-ETHYL-6-[4-(QUINOXALIN-2-YLAMINO)-BENZOYLAMINO]-HEXANOYLAMINO}-4-OXO-BUTYRIC+ACID'>4QB</scene></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">CASP1, IL1BC, IL1BCE ([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=1rwn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rwn OCA], [https://pdbe.org/1rwn PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rwn RCSB], [https://www.ebi.ac.uk/pdbsum/1rwn PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rwn 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-1 Caspase-1], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.4.22.36 3.4.22.36] </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=1rwn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rwn OCA], [http://pdbe.org/1rwn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=1rwn RCSB], [http://www.ebi.ac.uk/pdbsum/1rwn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=1rwn ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/CASP1_HUMAN CASP1_HUMAN]] Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis.<ref>PMID:7876192</ref> <ref>PMID:15498465</ref> | + | [https://www.uniprot.org/uniprot/CASP1_HUMAN CASP1_HUMAN] Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis.<ref>PMID:7876192</ref> <ref>PMID:15498465</ref> |
| | == Evolutionary Conservation == | | == Evolutionary Conservation == |
| | [[Image:Consurf_key_small.gif|200px|right]] | | [[Image:Consurf_key_small.gif|200px|right]] |
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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-1]] | + | [[Category: Homo sapiens]] |
| - | [[Category: Human]] | + | [[Category: Large Structures]] |
| - | [[Category: Brien, T O]] | + | [[Category: Fahr BT]] |
| - | [[Category: Fahr, B T]] | + | [[Category: O'Brien T]] |
| - | [[Category: Romanowski, M J]] | + | [[Category: Romanowski MJ]] |
| - | [[Category: Hydrolase]]
| + | |
| - | [[Category: Protein-small molecule inhibitor complex]]
| + | |
| Structural highlights
Function
CASP1_HUMAN Thiol protease that cleaves IL-1 beta between an Asp and an Ala, releasing the mature cytokine which is involved in a variety of inflammatory processes. Important for defense against pathogens. Cleaves and activates sterol regulatory element binding proteins (SREBPs). Can also promote apoptosis.[1] [2]
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
Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1beta but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site.
Structural analysis of caspase-1 inhibitors derived from Tethering.,O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:16511067[3]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Alnemri ES, Fernandes-Alnemri T, Litwack G. Cloning and expression of four novel isoforms of human interleukin-1 beta converting enzyme with different apoptotic activities. J Biol Chem. 1995 Mar 3;270(9):4312-7. PMID:7876192
- ↑ Feng Q, Li P, Leung PC, Auersperg N. Caspase-1zeta, a new splice variant of the caspase-1 gene. Genomics. 2004 Sep;84(3):587-91. PMID:15498465 doi:http://dx.doi.org/S0888-7543(04)00161-2
- ↑ O'Brien T, Fahr BT, Sopko MM, Lam JW, Waal ND, Raimundo BC, Purkey HE, Pham P, Romanowski MJ. Structural analysis of caspase-1 inhibitors derived from Tethering. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:16511067 doi:10.1107/S1744309105010109
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