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PDBsum entry 2vsl
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References listed in PDB file
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Key reference
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Title
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Interaction of a cyclic, Bivalent smac mimetic with the X-Linked inhibitor of apoptosis protein.
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Authors
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Z.Nikolovska-Coleska,
J.L.Meagher,
S.Jiang,
C.Y.Yang,
S.Qiu,
P.P.Roller,
J.A.Stuckey,
S.Wang.
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Ref.
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Biochemistry, 2008,
47,
9811-9824.
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PubMed id
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Abstract
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We have designed and synthesized a cyclic, bivalent Smac mimetic (compound 3)
and characterized its interaction with the X-linked inhibitor of apoptosis
protein (XIAP). Compound 3 binds to XIAP containing both BIR2 and BIR3 domains
with a biphasic dose-response curve representing two binding sites with IC 50
values of 0.5 and 406 nM, respectively. Compound 3 binds to XIAPs containing the
BIR3-only and BIR2-only domain with K i values of 4 nM and 4.4 microM,
respectively. Gel filtration experiments using wild-type and mutated XIAPs
showed that 3 forms a 1:2 stoichiometric complex with XIAP containing the
BIR3-only domain. However, it forms a 1:1 stoichiometric complex with XIAP
containing both BIR2 and BIR3 domains, and both BIR domains are involved in the
binding. Compound 3 efficiently antagonizes inhibition of XIAP in a cell-free
functional assay and is >200 times more potent than its corresponding
monovalent compound 2. Determination of the crystal structure of 3 in complex
with the XIAP BIR3 domain confirms that 3 induces homodimerization of the XIAP
BIR3 domain and provides a structural basis for the cooperative binding of one
molecule of compound 3 to two XIAP BIR3 molecules. On the basis of this crystal
structure, a binding model of XIAP containing both BIR2 and BIR3 domains and 3
was constructed, which sheds light on the ability of 3 to relieve the inhibition
of XIAP with not only caspase-9 but also caspase-3/-7. Compound 3 is
cell-permeable, effectively activates caspases in whole cells, and potently
inhibits cancer cell growth. Compound 3 is a useful biochemical and
pharmacological tool for further elucidating the role of XIAP in regulation of
apoptosis and represents a promising lead compound for the design of potent,
cell-permeable Smac mimetics for cancer treatment.
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