1sc3: Difference between revisions

Revision as of 15:59, 21 February 2008

Crystal structure of the human caspase-1 C285A mutant in complex with malonate

OverviewOverview

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.

About this StructureAbout this Structure

1SC3 is a Protein complex structure of sequences from Homo sapiens with as ligand. Active as Caspase-1, with EC number 3.4.22.36 Full crystallographic information is available from OCA.

ReferenceReference

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

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OCA

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-[[Image:1sc3.gif|left|200px]]<br />
+[[Image:1sc3.gif|left|200px]]<br /><applet load="1sc3" size="350" color="white" frame="true" align="right" spinBox="true"
-<applet load="1sc3" size="450" color="white" frame="true" align="right" spinBox="true"
 caption="1sc3, resolution 1.80&Aring;" />
 '''Crystal structure of the human caspase-1 C285A mutant in complex with malonate'''<br />
 ==Overview==
-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.
+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.
 ==About this Structure==
-SC3 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 MLI 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=1SC3 OCA].
+SC3 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 <scene name='pdbligand=MLI:'>MLI</scene> 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://oca.weizmann.ac.il/oca-bin/ocashort?id=1SC3 OCA].
 ==Reference==
@@ Line 15: / Line 14: @@
 [[Category: Homo sapiens]]
 [[Category: Protein complex]]
-[[Category: Brien, T.O.]]
+[[Category: Brien, T O.]]
-[[Category: McDowell, R.S.]]
+[[Category: McDowell, R S.]]
-[[Category: Romanowski, M.J.]]
+[[Category: Romanowski, M J.]]
-[[Category: Scheer, J.M.]]
+[[Category: Scheer, J M.]]
 [[Category: MLI]]
 [[Category: malonate-bound caspase-1]]
-''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 19:12:23 2007''
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