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PDBsum entry 4hqr
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Hydrolase/hydrolase inhibitor
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PDB id
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4hqr
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References listed in PDB file
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Key reference
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Title
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Structural asymmetry of procaspase-7 bound to a specific inhibitor.
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Authors
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H.J.Kang,
Y.M.Lee,
K.H.Bae,
S.J.Kim,
S.J.Chung.
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Ref.
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Acta Crystallogr D Biol Crystallogr, 2013,
69,
1514-1521.
[DOI no: ]
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PubMed id
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Abstract
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Caspase-7 is expressed as a proenzyme and is activated by initiator caspases
upon the transmission of cell-death signals. Despite extensive structural and
biochemical analyses, many questions regarding the mechanism of caspase-7
activation remain unanswered. Caspase-7 is auto-activated during overexpression
in Escherichia coli, even in the absence of initiator caspases, indicating that
procaspase-7 has intrinsic catalytic activity. When variants of procaspase-7
with altered L2 loops were prepared, a variant with six inserted amino acids
showed meaningful catalytic activity which was inhibited by Ac-DEVD-CHO. The
kinetic constants of the procaspase-7 variant were determined and its
three-dimensional structure was solved with and without bound inhibitor. The
homodimeric procaspase-7 bound to the inhibitor revealed an asymmetry. One
monomer formed a complete active site bound to the inhibitor in collaboration
with the L2 loop from the other monomer, whereas the other monomer had an
incomplete active site despite the bound inhibitor. Consequently, the two L2
loops in homodimeric procaspase-7 served as inherent L2 and L2' loops forming
one complete active site. These data represent the first three-dimensional
structure of a procaspase-7 variant bound to a specific inhibitor, Ac-DEVD-CHO,
and provide insight into the folding mechanism during caspase-7 activation and
the basal activity level of procaspase-7.
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