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PDBsum entry 4ec4
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Apoptosis inhibitor
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PDB id
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4ec4
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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 insight into inhibitor of apoptosis proteins recognition by a potent divalent smac-Mimetic.
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Authors
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F.Cossu,
M.Milani,
P.Vachette,
F.Malvezzi,
S.Grassi,
D.Lecis,
D.Delia,
C.Drago,
P.Seneci,
M.Bolognesi,
E.Mastrangelo.
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Ref.
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Plos One, 2012,
7,
e49527.
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PubMed id
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Abstract
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Genetic alterations enhancing cell survival and suppressing apoptosis are
hallmarks of cancer that significantly reduce the efficacy of chemotherapy or
radiotherapy. The Inhibitor of Apoptosis Protein (IAP) family hosts conserved
proteins in the apoptotic pathway whose over-expression, frequently found in
tumours, potentiates survival and resistance to anticancer agents. In humans,
IAPs comprise eight members hosting one or more structural Baculoviral IAP
Repeat (BIR) domains. Cellular IAPs (cIAP1 and 2) indirectly inhibit caspase-8
activation, and regulate both the canonical and the non-canonical NF-κB
signaling pathways. In contrast to cIAPs, XIAP (X chromosome-linked Inhibitor of
Apoptosis Protein) inhibits directly the effector caspases-3 and -7 through its
BIR2 domain, and initiator caspase-9 through its BIR3 domain; molecular docking
studies suggested that Smac/DIABLO antagonizes XIAP by simultaneously targeting
both BIR2 and BIR3 domains. Here we report analytical gel filtration,
crystallographic and SAXS experiments on cIAP1-BIR3, XIAP-BIR3 and XIAP-BIR2BIR3
domains, alone and in the presence of compound 9a, a divalent homodimeric Smac
mimetic. 9a is shown to bind two BIR domains inter- (in the case of two BIR3)
and intra-molecularly (in the case of XIAP-BIR2BIR3), with higher affinity for
cIAP1-BIR3, relative to XIAP-BIR3. Despite the different crystal lattice
packing, 9a maintains a right handed helical conformation in both cIAP1-BIR3 and
XIAP-BIR3 crystals, that is likely conserved in solution as shown by SAXS data.
Our structural results demonstrate that the 9a linker length, its conformational
degrees of freedom and its hydrophobicity, warrant an overall compact structure
with optimal solvent exposure of its two active moieties for IAPs binding. Our
results show that 9a is a good candidate for pre-clinical and clinical studies,
worth of further investigations in the field of cancer therapy.
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