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PDBsum entry 1sc3
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Contents |
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* Residue conservation analysis
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References listed in PDB file
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Key reference
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Title
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Crystal structures of a ligand-Free and malonate-Bound human caspase-1: implications for the mechanism of substrate binding.
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Authors
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M.J.Romanowski,
J.M.Scheer,
T.O'Brien,
R.S.Mcdowell.
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Ref.
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Structure, 2004,
12,
1361-1371.
[DOI no: ]
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PubMed id
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Abstract
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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.
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Figure 3.
Figure 3. The Central Cavity at the Dimer-Dimer Interface
in Human Caspase-1The active site is indicated by orange
ellipses; the dimer-dimer interface is enclosed by a yellow
box.(A) Surface representation of the residues surrounding the
closed cavity in the enzyme complexed with an active-site
inhibitor.(B) Surface representation of the residues surrounding
the open cavity in the active-site ligand-free enzyme.
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The above figure is
reprinted
by permission from Cell Press:
Structure
(2004,
12,
1361-1371)
copyright 2004.
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