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PDBsum entry 2p2c
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Contents |
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(+ 0 more)
162 a.a.
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96 a.a.
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158 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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Inhibition of caspase-2 by a designed ankyrin repeat protein: specificity, Structure, And inhibition mechanism.
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Authors
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A.Schweizer,
H.Roschitzki-Voser,
P.Amstutz,
C.Briand,
M.Gulotti-Georgieva,
E.Prenosil,
H.K.Binz,
G.Capitani,
A.Baici,
A.Pl?ckthun,
M.G.Gr?tter.
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Ref.
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Structure, 2007,
15,
625-636.
[DOI no: ]
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PubMed id
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Abstract
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Specific and potent caspase inhibitors are indispensable for the dissection of
the intricate pathways leading to apoptosis. We selected a designed ankyrin
repeat protein (DARPin) from a combinatorial library that inhibits caspase-2 in
vitro with a subnanomolar inhibition constant and, in contrast to the peptidic
caspase inhibitors, with very high specificity for this particular caspase. The
crystal structure of this inhibitor (AR_F8) in complex with caspase-2 reveals
the molecular basis for the specificity and, together with kinetic analyses, the
allosteric mechanism of inhibition. The structure also shows a conformation of
the active site that can be exploited for the design of inhibitory compounds.
AR_F8 is a specific inhibitor of an initiator caspase and has the potential to
help identify the function of caspase-2 in the complex biological apoptotic
signaling network.
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Figure 2.
Figure 2. Stereo Representation of the Structure of the
Caspase-2/AR_F8 Complex
Caspase-2 is shown in dark blue (α
subunit) and light blue (β subunit), and AR_F8 is shown in
salmon. AR_F8 is bound to the back side of the
active-site-forming loop 381 (see Figure 5C) of each caspase-2
monomer. Termini and loops affected by binding of AR_F8 are
shown in red. The active-site cysteine (Cys285) and the
intersubunit disulfide bond are shown in yellow.
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Figure 3.
Figure 3. Molecular Interactions between AR_F8 and Caspase-2
Stereo representation of the caspase-2/AR_F8 interface
rotated  vert,
similar 90° from the standard orientation, viewed from the
back plane of the caspase, displaying hydrogen bonds (green,
dotted lines) and hydrophobic interactions. Interacting residues
of AR_F8 are shown in red; those of caspase-2 are shown in blue.
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The above figures are
reprinted
by permission from Cell Press:
Structure
(2007,
15,
625-636)
copyright 2007.
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