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PDBsum entry 2dko
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Hydrolase/hydrolase inhibitor
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PDB id
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2dko
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References listed in PDB file
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Key reference
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Title
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Extended substrate recognition in caspase-3 revealed by high resolution x-Ray structure analysis.
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Authors
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R.Ganesan,
P.R.Mittl,
S.Jelakovic,
M.G.Grütter.
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Ref.
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J Mol Biol, 2006,
359,
1378-1388.
[DOI no: ]
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PubMed id
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Abstract
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Caspases are cysteine proteases involved in the signalling cascades of
programmed cell death in which caspase-3 plays a central role, since it
propagates death signals from intrinsic and extrinsic stimuli to downstream
targets. The atomic resolution (1.06 Angstroms) crystal structure of the
caspase-3 DEVD-cmk complex reveals the structural basis for substrate
selectivity in the S4 pocket. A low-barrier hydrogen bond is observed between
the side-chains of the P4 inhibitor aspartic acid and Asp179 of the N-terminal
tail of the symmetry related p12 subunit. Site-directed mutagenesis of Asp179
confirmed the significance of this residue in substrate recognition. In the 1.06
Angstroms crystal structure, a radiation damage induced rearrangement of the
inhibitor methylketone moiety was observed. The carbon atom that in a substrate
would represent the scissile peptide bond carbonyl carbon clearly shows a
tetrahedral coordination and resembles the postulated tetrahedral intermediate
of the acylation reaction.
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Figure 3.
Figure 3. Superposition of active sites in the 1.06 Å
and 1.7 Å resolution structures with carbon atoms shown in
cyan and magenta, respectively. The F[obs](1.06 Å)
-(F[obs](1.7 Å)) (f[calc]^(1.06 Å)) map was
contoured at +5s (green) and -5s (red) levels. The 2F[obs](1.06
Å) -(F[calc]^(1.06 Å)) (f[calc]^(1.06 Å)) map
contoured at +3s is shown in grey.
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Figure 6.
Figure 6. Active site geometry of the (a) 1.7 Å and
(b) 1.06 Å resolution structures. Putative hydrogen bonds
and general distances are shown in red and grey, respectively.
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The above figures are
reprinted
by permission from Elsevier:
J Mol Biol
(2006,
359,
1378-1388)
copyright 2006.
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