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1rwm

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(New page: 200px<br /> <applet load="1rwm" size="450" color="white" frame="true" align="right" spinBox="true" caption="1rwm, resolution 2.70&Aring;" /> '''Crystal structure o...)
Current revision (06:09, 23 August 2023) (edit) (undo)
 
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[[Image:1rwm.gif|left|200px]]<br />
 
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<applet load="1rwm" size="450" color="white" frame="true" align="right" spinBox="true"
 
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caption="1rwm, resolution 2.70&Aring;" />
 
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'''Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5-{[4-(quinoxalin-2-ylamino)-benzoylamino]-methyl}-thiophen-2-yl)-acetylamino]-pentanoic acid'''<br />
 
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==Overview==
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==Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5-{[4-(quinoxalin-2-ylamino)-benzoylamino]-methyl}-thiophen-2-yl)-acetylamino]-pentanoic acid==
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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.
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<StructureSection load='1rwm' size='340' side='right'caption='[[1rwm]], [[Resolution|resolution]] 2.70&Aring;' scene=''>
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== Structural highlights ==
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<table><tr><td colspan='2'>[[1rwm]] 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=1RWM OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1RWM FirstGlance]. <br>
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</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.7&#8491;</td></tr>
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<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=Q2Y:4-OXO-3-[2-(5-{[4-(QUINOXALIN-2-YLAMINO)-BENZOYLAMINO]-METHYL}-THIOPHEN-2-YL)-ACETYLAMINO]-PENTANOIC+ACID'>Q2Y</scene></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=1rwm FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1rwm OCA], [https://pdbe.org/1rwm PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1rwm RCSB], [https://www.ebi.ac.uk/pdbsum/1rwm PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1rwm ProSAT]</span></td></tr>
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</table>
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== Function ==
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[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>
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== Evolutionary Conservation ==
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[[Image:Consurf_key_small.gif|200px|right]]
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Check<jmol>
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<jmolCheckbox>
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<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/rw/1rwm_consurf.spt"</scriptWhenChecked>
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<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked>
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<text>to colour the structure by Evolutionary Conservation</text>
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</jmolCheckbox>
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</jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1rwm ConSurf].
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<div style="clear:both"></div>
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<div style="background-color:#fffaf0;">
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== Publication Abstract from PubMed ==
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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.
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==About this Structure==
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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<ref>PMID:16511067</ref>
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1RWM is a [http://en.wikipedia.org/wiki/Protein_complex Protein complex] structure of sequences from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens] with Q2Y as [http://en.wikipedia.org/wiki/ligand ligand]. Active as [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] Full crystallographic information is available from [http://ispc.weizmann.ac.il/oca-bin/ocashort?id=1RWM OCA].
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==Reference==
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From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
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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 Crystallograph Sect F Struct Biol Cryst Commun. 2005 May 1;61(Pt, 5):451-8. Epub 2005 Apr 9. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=16511067 16511067]
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</div>
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[[Category: Caspase-1]]
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<div class="pdbe-citations 1rwm" style="background-color:#fffaf0;"></div>
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[[Category: Homo sapiens]]
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[[Category: Protein complex]]
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[[Category: Brien, T.O.]]
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[[Category: Fahr, B.T.]]
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[[Category: Romanowski, M.J.]]
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[[Category: Waal, N.D.]]
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[[Category: Q2Y]]
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[[Category: protein-small molecule inhibitor complex]]
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''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:07:39 2007''
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==See Also==
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*[[Caspase 3D structures|Caspase 3D structures]]
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== References ==
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<references/>
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__TOC__
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</StructureSection>
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[[Category: Homo sapiens]]
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[[Category: Large Structures]]
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[[Category: Fahr BT]]
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[[Category: O'Brien T]]
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[[Category: Romanowski MJ]]
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[[Category: Waal ND]]

Current revision

Crystal structure of human caspase-1 in complex with 4-oxo-3-[2-(5-{[4-(quinoxalin-2-ylamino)-benzoylamino]-methyl}-thiophen-2-yl)-acetylamino]-pentanoic acid

PDB ID 1rwm

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