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==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==
==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]] 1.80&Aring;' scene=''>
<StructureSection load='6f6r' size='340' side='right'caption='[[6f6r]], [[Resolution|resolution]] 1.80&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
<table><tr><td colspan='2'>[[6f6r]] 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=6F6R OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6F6R FirstGlance]. <br>
<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='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><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>
</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 1.8&#8491;</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='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='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'>[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>
<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=6f6r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6f6r OCA], [http://pdbe.org/6f6r PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6f6r RCSB], [http://www.ebi.ac.uk/pdbsum/6f6r PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6f6r 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>  
<div style="background-color:#fffaf0;">
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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</div>
</div>
<div class="pdbe-citations 6f6r" style="background-color:#fffaf0;"></div>
<div class="pdbe-citations 6f6r" style="background-color:#fffaf0;"></div>
==See Also==
*[[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: Aubert, J]]
[[Category: Aubert J]]
[[Category: Aurelly, M]]
[[Category: Aurelly M]]
[[Category: Bouix-Peter, C]]
[[Category: Bouix-Peter C]]
[[Category: Brethon, A]]
[[Category: Brethon A]]
[[Category: Chambon, S]]
[[Category: Chambon S]]
[[Category: Chantalat, L]]
[[Category: Chantalat L]]
[[Category: Christin, O]]
[[Category: Christin O]]
[[Category: Clary, L]]
[[Category: Clary L]]
[[Category: Comino, C]]
[[Category: Comino C]]
[[Category: Dumais, L]]
[[Category: Dumais L]]
[[Category: El-Bazbouz, G]]
[[Category: El-Bazbouz G]]
[[Category: Fournier, J F]]
[[Category: Fournier JF]]
[[Category: Ghilini, A L]]
[[Category: Ghilini AL]]
[[Category: Harris, C S]]
[[Category: Harris CS]]
[[Category: Hennequin, L F]]
[[Category: Hennequin LF]]
[[Category: Isabet, T]]
[[Category: Isabet T]]
[[Category: Lardy, C]]
[[Category: Lardy C]]
[[Category: Luzy, A P]]
[[Category: Luzy AP]]
[[Category: Mathieu, C]]
[[Category: Mathieu C]]
[[Category: Mebrouk, K]]
[[Category: Mebrouk K]]
[[Category: Millois-Barbuis, C]]
[[Category: Millois-Barbuis C]]
[[Category: Orfila, D]]
[[Category: Orfila D]]
[[Category: Pascau, J]]
[[Category: Pascau J]]
[[Category: Pierre, R]]
[[Category: Pierre R]]
[[Category: Reverse, K]]
[[Category: Reverse K]]
[[Category: Roche, D]]
[[Category: Roche D]]
[[Category: Rodeschini, V]]
[[Category: Rodeschini V]]
[[Category: Talano, S]]
[[Category: Talano S]]
[[Category: Thoreau, E]]
[[Category: Thoreau E]]
[[Category: Hydrolase]]
[[Category: Inflammatory disease]]
[[Category: Nanomolar inhibitor]]
[[Category: Sp3 hybridization]]

Latest revision as of 15:37, 6 November 2024

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)-benzamideCrystal 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

Structural highlights

6f6r is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.8Å
Ligands:,
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

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]

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[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

See Also

References

  1. ↑ 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
  2. ↑ 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
  3. ↑ 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. Rational Drug Design of Topically Administered Caspase 1 Inhibitors for the Treatment of Inflammatory Acne. J Med Chem. 2018 Apr 24. doi: 10.1021/acs.jmedchem.8b00067. PMID:29648825 doi:http://dx.doi.org/10.1021/acs.jmedchem.8b00067

6f6r, resolution 1.80Å

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