Abstract
A small series of peptide mimics was designed and synthesized to contain a heterocyclic ring in place of the potentially labile N-terminal peptide bond of the tetrapeptide containing the Smac-XIAP-binding motif. Two Smac mimics were shown to bind to the BIR3 domain of XIAP with moderate affinity and one displayed increased activity in cells relative to the Smac peptides. The structures of BIR3-XIAP in complex with a Smac peptide and a peptide mimic were solved and analyzed to elucidate the structure-activity relationship surrounding the Smac-binding domain within BIR3-XIAP.
MeSH terms
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Apoptosis Regulatory Proteins
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Binding Sites / drug effects
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Cell Line
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Cell Survival
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Crystallography, X-Ray
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Heterocyclic Compounds / chemical synthesis
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Heterocyclic Compounds / pharmacology
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Humans
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Hydrogen Bonding
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Intracellular Signaling Peptides and Proteins / chemistry
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Intracellular Signaling Peptides and Proteins / drug effects
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Intracellular Signaling Peptides and Proteins / metabolism*
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Ligands
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Magnetic Resonance Spectroscopy
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Mitochondrial Proteins / chemistry
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Mitochondrial Proteins / drug effects
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Mitochondrial Proteins / metabolism*
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Models, Molecular
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Molecular Conformation
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Molecular Mimicry
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Structure-Activity Relationship
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Tetrazolium Salts
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Thiazoles
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X-Linked Inhibitor of Apoptosis Protein / chemistry
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X-Linked Inhibitor of Apoptosis Protein / drug effects
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X-Linked Inhibitor of Apoptosis Protein / metabolism*
Substances
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Apoptosis Regulatory Proteins
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DIABLO protein, human
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Heterocyclic Compounds
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Intracellular Signaling Peptides and Proteins
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Ligands
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Mitochondrial Proteins
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Tetrazolium Salts
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Thiazoles
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X-Linked Inhibitor of Apoptosis Protein
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thiazolyl blue