title: Targeting the conformational transitions of MDM2 and MDMX: insights into key residues affecting p53 recognition.
abstract: The oncogenic proteins MDM2 and MDMX have distinct and critical roles in the control of the activity of the p53 tumor suppressor protein. Recently, we have used spatial coarse graining simulations to analyze the conformational transitions manifest in the p53 recognition of MDM2 and MDMX. These conformational movements are different between MDM2 and MDMX and unveil the presence of conserved and nonconserved interactions in the p53 binding cleft that may be exploited in the design of selective and dual modulators of the oncogenic proteins. In this study, we investigate the conformational profiles of apo- and p53-bound states of MDM2 and MDMX using molecular dynamic simulations along a time scale of 60 ns. The analysis of the trajectories is instrumental to discuss energetical and conformational aspects of p53 recognition and to point out specific key residues whose conformational shifts have crucial roles in affecting the apo- and p53-bound states of MDM2 and MDMX. Among these, in particular, linear discriminant analyses identify diverse conformations of Y99/Y100 (MDMX/MDM2) as markers of the apo- and p53-bound states of the oncogenic proteins. The results of this study shed further light on different p53 recognition in MDM2 and MDMX and may prove useful for the design and identification of new potent and selective synthetic modulators of p53-MDM2/MDMX interactions.
authors.affiliation: Dipartimento di Chimica e Tecnologia del Farmaco, Università di Perugia, 06123 Perugia, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Carotti
authors.forename: Antonio
authors.initials: A
authors.lastname: Macchiarulo
authors.forename: Nicola
authors.initials: N
authors.lastname: Giacchè
authors.forename: Roberto
authors.initials: R
authors.lastname: Pellicciari
mesh_terms: D001665:Binding Sites; D018797:Cell Cycle Proteins; D019295:Computational Biology / Q000379:methods; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry*; D011485:Protein Binding; D011487:Protein Conformation; D025941:Protein Interaction Mapping; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry*; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry*; D012984:Software; D055672:Static Electricity; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry*
chemical_list: D018797:Cell Cycle Proteins; C482775:MDM4 protein, human; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2