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PDBsum entry 4lsz
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Contents |
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140 a.a.
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94 a.a.
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153 a.a.
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References listed in PDB file
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Key reference
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Title
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Combined inhibition of caspase 3 and caspase 7 by two highly selective darpins slows down cellular demise.
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Authors
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A.Flütsch,
R.Ackermann,
T.Schroeder,
M.Lukarska,
G.J.Hausammann,
C.Weinert,
C.Briand,
M.G.Grütter.
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Ref.
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Biochem J, 2014,
461,
279-290.
[DOI no: ]
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PubMed id
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Abstract
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Caspases play important roles during apoptosis, inflammation and proliferation.
The high homology among family members makes selective targeting of individual
caspases difficult, which is necessary to precisely define the role of these
enzymes. We have selected caspase-7-specific binders from a library of DARPins
(designed ankyrin repeat proteins). The DARPins D7.18 and D7.43 bind
specifically to procaspase 7 and active caspase 7, but not to other members of
the family. Binding of the DARPins does not affect the active enzyme, but
interferes with its activation by other caspases. The crystal structure of the
caspase 7-D7.18 complex elucidates the high selectivity and the mode of
inhibition. Combining these caspase-7-specific DARPins with the previously
reported caspase-3-inhibitory DARPin D3.4S76R reduces the activity of caspase 3
and 7 in double-transfected HeLa cells during apoptosis. In addition, these
cells showed less susceptibility to TRAIL (tumour-necrosis-factor-related
apoptosis-inducing ligand)-induced apoptosis in living cell experiments. D7.18
and D7.43 are therefore novel tools for in vitro studies on procaspase 7
activation as well as for clarifying the role of its activation in different
cellular processes. If applied in combination with D3.4S76R, they represent an
excellent instrument to increase our understanding of these enzymes during
various cellular processes.
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