title: Chemical states of the N-terminal "lid" of MDM2 regulate p53 binding: simulations reveal complexities of modulation.
abstract: Phosphorylation of S17 in the N-terminal "lid" of MDM2 (residues 1-24) is proposed to regulate the binding of p53. The lid is composed of an intrinsically disordered peptide motif that is not resolved in the crystal structure of the MDM2 N-terminal domain. Molecular dynamics simulations of MDM2 provide novel insight into how the lid undergoes complex dynamics depending on its phosphorylation state that have not been revealed by NMR analyses. The difference in charges between the phosphate and the phosphomimetic 'Asp' and the change in shape from tetrahedral to planar are manifested in differences in strengths and durations of interactions that appear to modulate access of the binding site to ligands and peptides differentially. These findings unveil the complexities that underlie protein-protein interactions and reconcile some differences between the biochemical and NMR data suggesting that lid mutation or deletion can change the specific activity of MDM2 and provide concepts for future approaches to evaluate the effects of S17 modification on p53 binding.
authors.affiliation: Bioinformatics Institute (A-STAR), Singapore. sgducd@gmail.com
authors.forename: Shubhra Ghosh
authors.initials: SG
authors.lastname: Dastidar
authors.forename: Devanathan
authors.initials: D
authors.lastname: Raghunathan
authors.forename: Judith
authors.initials: J
authors.lastname: Nicholson
authors.forename: Ted R
authors.initials: TR
authors.lastname: Hupp
authors.forename: David P
authors.initials: DP
authors.lastname: Lane
authors.forename: Chandra S
authors.initials: CS
authors.lastname: Verma
mesh_terms: D020816:Amino Acid Motifs; D003198:Computer Simulation; D006801:Humans; D056004:Molecular Dynamics Simulation; D010766:Phosphorylation; D011485:Protein Binding / Q000502:physiology; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2