Abstract
Atomistic simulations of a set of stapled peptides derived from the transactivation domain of p53 (designed by Verdine & colleagues, JACS 2007 129:2456) and complexed to MDM2 reveal that the good binders are uniquely characterized by higher helicity and by extensive interactions between the hydrocarbon staples and the MDM2 surface; in contrast the poor binders have reduced helicity and their staples are mostly solvent exposed. Our studies also find that the best binders can also potentially inhibit MDMX with similar affinities, suggesting that such stapled peptides can be evolved for dual inhibition with therapeutic potential.
MeSH terms
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Amino Acid Sequence
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Cell Cycle Proteins
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Humans
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Molecular Dynamics Simulation
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Molecular Sequence Data
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Nuclear Proteins / antagonists & inhibitors
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Nuclear Proteins / metabolism
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Peptides / chemistry*
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Protein Binding
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / metabolism
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Proto-Oncogene Proteins c-mdm2 / chemistry
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Proto-Oncogene Proteins c-mdm2 / metabolism
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Tumor Suppressor Protein p53 / chemistry*
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Tumor Suppressor Protein p53 / metabolism
Substances
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Cell Cycle Proteins
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MDM4 protein, human
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Nuclear Proteins
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Peptides
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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MDM2 protein, human
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Proto-Oncogene Proteins c-mdm2