Abstract
The tumour suppressor p53 is the most frequently mutated gene in human cancer. Reactivation of mutant p53 by small molecules is an exciting potential cancer therapy. Although several compounds restore wild-type function to mutant p53, their binding sites and mechanisms of action are elusive. Here computational methods identify a transiently open binding pocket between loop L1 and sheet S3 of the p53 core domain. Mutation of residue Cys124, located at the centre of the pocket, abolishes p53 reactivation of mutant R175H by PRIMA-1, a known reactivation compound. Ensemble-based virtual screening against this newly revealed pocket selects stictic acid as a potential p53 reactivation compound. In human osteosarcoma cells, stictic acid exhibits dose-dependent reactivation of p21 expression for mutant R175H more strongly than does PRIMA-1. These results indicate the L1/S3 pocket as a target for pharmaceutical reactivation of p53 mutants.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Apoptosis Regulatory Proteins / metabolism
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Aza Compounds / pharmacology
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Binding Sites
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Bridged Bicyclo Compounds, Heterocyclic / pharmacology
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Cell Line, Tumor
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Computational Biology / methods*
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Cyclin-Dependent Kinase Inhibitor p21 / genetics
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Cyclin-Dependent Kinase Inhibitor p21 / metabolism
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Cysteine / genetics
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Heterocyclic Compounds, 4 or More Rings / chemistry
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Heterocyclic Compounds, 4 or More Rings / pharmacology
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Humans
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Molecular Dynamics Simulation
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Mutant Proteins / chemistry*
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Mutant Proteins / metabolism*
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Oxepins / chemistry
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Oxepins / pharmacology
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Protein Stability / drug effects
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Proto-Oncogene Proteins / metabolism
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Reproducibility of Results
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Structure-Activity Relationship
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Transcription, Genetic / drug effects
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Tumor Suppressor Protein p53 / chemistry*
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Tumor Suppressor Protein p53 / genetics
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Tumor Suppressor Protein p53 / metabolism*
Substances
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Apoptosis Regulatory Proteins
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Aza Compounds
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BBC3 protein, human
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Bridged Bicyclo Compounds, Heterocyclic
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Cyclin-Dependent Kinase Inhibitor p21
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Heterocyclic Compounds, 4 or More Rings
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Mutant Proteins
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Oxepins
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Proto-Oncogene Proteins
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Tumor Suppressor Protein p53
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stictic acid
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2,2-bis(hydroxymethyl)-1-azabicyclo(2,2,2,)octan-3-one
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Cysteine