6f6r
From Proteopedia
(Difference between revisions)
(New page: '''Unreleased structure''' The entry 6f6r is ON HOLD until sometime in the future Authors: Isabet, T., Chantalat, L., Thoreau, E. Description: Crystal structure of human Caspase-1 with...) |
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of human Caspase-1 with N-{3-[1-((S)-2-Hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-(quinoxalin-2-ylamino)-benzamide== | |
| + | <StructureSection load='6f6r' size='340' side='right'caption='[[6f6r]], [[Resolution|resolution]] 1.80Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[6f6r]] 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=6F6R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6F6R FirstGlance]. <br> | ||
| + | </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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CVE:(3~{S})-3-[[(2~{R})-2-[3-methyl-2,6-bis(oxidanylidene)-5-[[4-(quinoxalin-2-ylamino)phenyl]carbonylamino]pyrimidin-1-yl]propanoyl]amino]-4-oxidanyl-butanoic+acid'>CVE</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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=6f6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f6r OCA], [https://pdbe.org/6f6r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6f6r RCSB], [https://www.ebi.ac.uk/pdbsum/6f6r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6f6r ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [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> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | The use of an interleukin beta antibody is currently being investigated in the clinic for the treatment of acne, a dermatological disorder affecting 650M persons globally. Inhibiting the protease responsible for the cleavage of inactive pro-IL1beta into active IL-1beta, caspase-1, could be an alternative small molecule approach. This report describes the discovery of uracil 20, a potent (38 nM in THP1 cells assay) caspase-1 inhibitor for the topical treatment of inflammatory acne. The uracil series was designed according to a published caspase-1 pharmacophore model involving a reactive warhead in P1 for covalent reversible inhibition and an aryl moiety in P4 for selectivity against the apoptotic caspases. Reversibility was assessed in an enzymatic dilution assay or by using different substrate concentrations. In addition to classical structure-activity-relationship exploration, topical administration challenges such as phototoxicity, organic and aqueous solubility, chemical stability in solution, and skin metabolic stability are discussed and successfully resolved. | ||
| - | + | Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne.,Fournier JF, Clary L, Chambon S, Dumais L, Harris CS, Millois C, Pierre R, Talano S, Thoreau E, Aubert J, Aurelly M, Bouix-Peter C, Brethon A, Chantalat L, Christin O, Comino C, El-Bazbouz G, Ghilini AL, Isabet T, Lardy C, Luzy AP, Mathieu C, Mebrouk K, Orfila D, Pascau J, Reverse K, Roche D, Rodeschini V, Hennequin LF J Med Chem. 2018 Apr 24. doi: 10.1021/acs.jmedchem.8b00067. PMID:29648825<ref>PMID:29648825</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Isabet | + | <div class="pdbe-citations 6f6r" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | |
| - | [[Category: | + | ==See Also== |
| + | *[[Caspase 3D structures|Caspase 3D structures]] | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Homo sapiens]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Aubert J]] | ||
| + | [[Category: Aurelly M]] | ||
| + | [[Category: Bouix-Peter C]] | ||
| + | [[Category: Brethon A]] | ||
| + | [[Category: Chambon S]] | ||
| + | [[Category: Chantalat L]] | ||
| + | [[Category: Christin O]] | ||
| + | [[Category: Clary L]] | ||
| + | [[Category: Comino C]] | ||
| + | [[Category: Dumais L]] | ||
| + | [[Category: El-Bazbouz G]] | ||
| + | [[Category: Fournier JF]] | ||
| + | [[Category: Ghilini AL]] | ||
| + | [[Category: Harris CS]] | ||
| + | [[Category: Hennequin LF]] | ||
| + | [[Category: Isabet T]] | ||
| + | [[Category: Lardy C]] | ||
| + | [[Category: Luzy AP]] | ||
| + | [[Category: Mathieu C]] | ||
| + | [[Category: Mebrouk K]] | ||
| + | [[Category: Millois-Barbuis C]] | ||
| + | [[Category: Orfila D]] | ||
| + | [[Category: Pascau J]] | ||
| + | [[Category: Pierre R]] | ||
| + | [[Category: Reverse K]] | ||
| + | [[Category: Roche D]] | ||
| + | [[Category: Rodeschini V]] | ||
| + | [[Category: Talano S]] | ||
| + | [[Category: Thoreau E]] | ||
Current revision
Crystal structure of human Caspase-1 with N-{3-[1-((S)-2-Hydroxy-5-oxo-tetrahydro-furan-3-ylcarbamoyl)-ethyl]-1-methyl-2,4-dioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl}-4-(quinoxalin-2-ylamino)-benzamide
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Categories: Homo sapiens | Large Structures | Aubert J | Aurelly M | Bouix-Peter C | Brethon A | Chambon S | Chantalat L | Christin O | Clary L | Comino C | Dumais L | El-Bazbouz G | Fournier JF | Ghilini AL | Harris CS | Hennequin LF | Isabet T | Lardy C | Luzy AP | Mathieu C | Mebrouk K | Millois-Barbuis C | Orfila D | Pascau J | Pierre R | Reverse K | Roche D | Rodeschini V | Talano S | Thoreau E
