title: Stapled peptides in the p53 pathway: computer simulations reveal novel interactions of the staples with the target protein.
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.
authors.affiliation: Bioinformatics Institute, Matrix, Singapore.
authors.forename: Thomas Leonard
authors.initials: TL
authors.lastname: Joseph
authors.forename: David
authors.initials: D
authors.lastname: Lane
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
mesh_terms: D000595:Amino Acid Sequence; D018797:Cell Cycle Proteins; D006801:Humans; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D010455:Peptides / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D010455:Peptides; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2