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==Crystal structure of the human caspase-1 C285A mutant in complex with malonate== | |||
<StructureSection load='1sc3' size='340' side='right'caption='[[1sc3]], [[Resolution|resolution]] 1.80Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[1sc3]] 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=1SC3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1SC3 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=MLI:MALONATE+ION'>MLI</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=1sc3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1sc3 OCA], [https://pdbe.org/1sc3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1sc3 RCSB], [https://www.ebi.ac.uk/pdbsum/1sc3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1sc3 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> | |||
== Evolutionary Conservation == | |||
[[Image:Consurf_key_small.gif|200px|right]] | |||
Check<jmol> | |||
<jmolCheckbox> | |||
<scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/sc/1sc3_consurf.spt"</scriptWhenChecked> | |||
<scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | |||
<text>to colour the structure by Evolutionary Conservation</text> | |||
</jmolCheckbox> | |||
</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=1sc3 ConSurf]. | |||
<div style="clear:both"></div> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Caspase-1, a mediator of the posttranslational processing of IL-1beta and IL-18, requires an aspartic acid in the P1 position of its substrates. The mechanisms of caspase-1 activation remain poorly understood despite numerous structures of the enzyme complexed with aspartate-based inhibitors. Here we report a crystal structure of ligand-free caspase-1 that displays dramatic rearrangements of loops defining the active site to generate a closed conformation that is incompatible with substrate binding. A structure of the enzyme complexed with malonate shows the protein in its open (active-site ligand-bound) conformation in which malonate reproduces the hydrogen bonding network observed in structures with covalent inhibitors. These results illustrate the essential function of the obligatory aspartate recognition element that opens the active site of caspase-1 to substrates and may be the determinant responsible for the conformational changes between ligand-free and -bound forms of the enzyme, and suggest a new approach for identifying novel aspartic acid mimetics. | |||
Crystal structures of a ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding.,Romanowski MJ, Scheer JM, O'Brien T, McDowell RS Structure. 2004 Aug;12(8):1361-71. PMID:15296730<ref>PMID:15296730</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 1sc3" style="background-color:#fffaf0;"></div> | |||
== | ==See Also== | ||
*[[Caspase 3D structures|Caspase 3D structures]] | |||
[ | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: | [[Category: Large Structures]] | ||
[[Category: | [[Category: McDowell RS]] | ||
[[Category: | [[Category: O'Brien T]] | ||
[[Category: Romanowski | [[Category: Romanowski MJ]] | ||
[[Category: Scheer | [[Category: Scheer JM]] | ||
Latest revision as of 09:15, 23 August 2023
Crystal structure of the human caspase-1 C285A mutant in complex with malonateCrystal structure of the human caspase-1 C285A mutant in complex with malonate
Structural highlights
FunctionCASP1_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 PubMedCaspase-1, a mediator of the posttranslational processing of IL-1beta and IL-18, requires an aspartic acid in the P1 position of its substrates. The mechanisms of caspase-1 activation remain poorly understood despite numerous structures of the enzyme complexed with aspartate-based inhibitors. Here we report a crystal structure of ligand-free caspase-1 that displays dramatic rearrangements of loops defining the active site to generate a closed conformation that is incompatible with substrate binding. A structure of the enzyme complexed with malonate shows the protein in its open (active-site ligand-bound) conformation in which malonate reproduces the hydrogen bonding network observed in structures with covalent inhibitors. These results illustrate the essential function of the obligatory aspartate recognition element that opens the active site of caspase-1 to substrates and may be the determinant responsible for the conformational changes between ligand-free and -bound forms of the enzyme, and suggest a new approach for identifying novel aspartic acid mimetics. Crystal structures of a ligand-free and malonate-bound human caspase-1: implications for the mechanism of substrate binding.,Romanowski MJ, Scheer JM, O'Brien T, McDowell RS Structure. 2004 Aug;12(8):1361-71. PMID:15296730[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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