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PDBsum entry 1pyo
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Hydrolase/hydrolase inhibitor
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PDB id
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1pyo
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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 structure of caspase-2, Apical initiator of the intrinsic apoptotic pathway.
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Authors
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A.Schweizer,
C.Briand,
M.G.Grutter.
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Ref.
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J Biol Chem, 2003,
278,
42441-42447.
[DOI no: ]
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PubMed id
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Abstract
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The cell death protease caspase-2 has recently been recognized as the most
apical caspase in the apoptotic cascade ignited during cell stress signaling.
Cytotoxic stress, such as that caused by cancer therapies, leads to activation
of caspase-2, which acts as a direct effector of the mitochondrion-dependent
apoptotic pathway resulting in programmed cell death. Here we report the x-ray
structure of caspase-2 in complex with the inhibitor
acetyl-Leu-Asp-Glu-Ser-Asp-aldehyde at 1.65-A resolution. Compared with other
caspases, significant structural differences prevail in the active site region
and the dimer interface. The structure reveals the hydrophobic properties of the
S5 specificity pocket, which is unique to caspase-2, and provides the details of
the inhibitor-protein interactions in subsites S1-S4. These features form the
basis of caspase-2 specificity and allow the design of caspase-2-directed
ligands for medical and analytical use. Another unique feature of caspase-2 is a
disulfide bridge at the dimer interface, which covalently links the two
monomers. Consistent with this finding, caspase-2 exists as a (p19/p12)2 dimer
in solution, even in the absence of substrates or inhibitors. The intersubunit
disulfide bridge stabilizes the dimeric form of caspase-2, whereas all other
long prodomain caspases exist as monomers in solution, and dimer formation is
driven by ligand binding. Therefore, the central disulfide bridge appears to
represent a novel way of dimer stabilization in caspases.
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Figure 2.
FIG. 2. Comparison of the enzyme inhibitor interaction
network of caspase-2 and caspase-3. Schematic drawing of the
caspase-2 Ac-LDESD-cho inhibitor complex (a) and the caspase-3
Ac-DEVD-cho inhibitor complex (b) (1PAU [PDB]
; 37) with hydrogen bond interactions drawn as dashed lines
(length: 2.6-3.4 Å). The diagram was produced by ChemDraw.
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Figure 3.
FIG. 3. Binding pockets of caspase-2, caspase-3, and
caspase-7. Comparison of the substrate binding region of
caspase-2/Ac-LDESD-cho (a) with caspase-3/Ac-DEVD-cho (b) (1PAU
[PDB]
; 37) and caspase-7/Ac-DEVD-cho (c) (1F1J [PDB]
; 35) using molecular surface representations. The inhibitors
are drawn as stick models, the P5 Leu is colored in green as
well as the N-terminal acetyl groups of the tetrapeptidic
inhibitors. Surfaces are colored according to their
electrostatic potential: positive and negative regions are
indicated in blue and red, respectively. The figures were
generated using the program GRASP (48).
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The above figures are
reprinted
by permission from the ASBMB:
J Biol Chem
(2003,
278,
42441-42447)
copyright 2003.
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