title: C-terminal substitution of MDM2 interacting peptides modulates binding affinity by distinctive mechanisms.
abstract: The complex between the proteins MDM2 and p53 is a promising drug target for cancer therapy. The residues 19-26 of p53 have been biochemically and structurally demonstrated to be a most critical region to maintain the association of MDM2 and p53. Variation of the amino acid sequence in this range obviously alters the binding affinity. Surprisingly, suitable substitutions contiguous to this region of the p53 peptides can yield tightly binding peptides. The peptide variants may differ by a single residue that vary little in their structural conformations and yet are characterized by large differences in their binding affinities. In this study a systematic analysis into the role of single C-terminal mutations of a 12 residue fragment of the p53 transactivation domain (TD) and an equivalent phage optimized peptide (12/1) were undertaken to elucidate their mechanistic and thermodynamic differences in interacting with the N-terminal of MDM2. The experimental results together with atomistically detailed dynamics simulations provide insight into the principles that govern peptide design protocols with regard to protein-protein interactions and peptidomimetic design.
authors: p53 Laboratory, Agency for Science, Technology and Research, Biopolis, Singapore. cjbrown@p53lab.a-star.edu.sg
authors: Christopher J
authors: CJ
authors: Brown
authors: Shubhra G
authors: SG
authors: Dastidar
authors: Soo T
authors: ST
authors: Quah
authors: Annie
authors: A
authors: Lim
authors: Brian
authors: B
authors: Chia
authors: Chandra S
authors: CS
authors: Verma
mesh_terms: D000595:Amino Acid Sequence; D002151:Calorimetry; D002942:Circular Dichroism; D003198:Computer Simulation; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism*; D011485:Protein Binding; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D010455:Peptides; D016159:Tumor Suppressor Protein p53; D051736:Proto-Oncogene Proteins c-mdm2