title: Structure of the stapled p53 peptide bound to Mdm2.
abstract: Mdm2 is a major negative regulator of the tumor suppressor p53 protein, a protein that plays a crucial role in maintaining genome integrity. Inactivation of p53 is the most prevalent defect in human cancers. Inhibitors of the Mdm2-p53 interaction that restore the functional p53 constitute potential nongenotoxic anticancer agents with a novel mode of action. We present here a 2.0 Å resolution structure of the Mdm2 protein with a bound stapled p53 peptide. Such peptides, which are conformationally and proteolytically stabilized with all-hydrocarbon staples, are an emerging class of biologics that are capable of disrupting protein-protein interactions and thus have broad therapeutic potential. The structure represents the first crystal structure of an i, i + 7 stapled peptide bound to its target and reveals that rather than acting solely as a passive conformational brace, a staple can intimately interact with the surface of a protein and augment the binding interface.
authors.affiliation: Max Planck Institute for Biochemistry, Am Klopferspitz 18, 82152 Martinsried, Germany.
authors.forename: Sohee
authors.initials: S
authors.lastname: Baek
authors.forename: Peter S
authors.initials: PS
authors.lastname: Kutchukian
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Verdine
authors.forename: Robert
authors.initials: R
authors.lastname: Huber
authors.forename: Tad A
authors.initials: TA
authors.lastname: Holak
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Grzegorz M
authors.initials: GM
authors.lastname: Popowicz
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D010446:Peptide Fragments; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2