title: Structural and sequential context of p53: A review of experimental and theoretical evidence.
abstract: Approximately 27 million people are suffering from cancer that contains either an inactivating missense mutation of TP53 gene or partially abrogated p53 signaling pathway. Concerted action of folded and intrinsically disordered domains accounts for multi-faceted role of p53. The intricacy of dynamic p53 structure is believed to shed light on its cellular activity for developing new cancer therapies. In this review, insights into structural details of p53, diverse single point mutations affecting its core domain, thermodynamic understanding and therapeutic strategies for pharmacological rescue of p53 function has been illustrated. An effort has been made here to bridge the structural and sequential evidence of p53 from experimental to computational studies. First, we focused on the individual domains and the crucial protein-protein or DNA-protein contacts that determine conformation and dynamic behavior of p53. Next, the oncogenic mutations associated with cancer and its contribution to thermodynamic fluctuation has been discussed. Thus the emerging anti-cancer strategies include targeting of destabilized cancer mutants with selective inhibition of its negative regulators. Recent advances in development of small molecule inhibitors and peptides exploiting p53-MDM2 interaction has been included. In a nutshell, this review attempts to describe structural biology of p53 which provide new openings for structure-guided rescue.
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India.
authors.forename: Taniya
authors.initials: T
authors.lastname: Saha
authors.affiliation: Division of Biophysics, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India.
authors.forename: Rajiv K
authors.initials: RK
authors.lastname: Kar
authors.affiliation: Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata 700054, India. Electronic address: gauri@jcbose.ac.in.
authors.forename: Gaurisankar
authors.initials: G
authors.lastname: Sa
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*; D006801:Humans; D008956:Models, Chemical; D056004:Molecular Dynamics Simulation; D008969:Molecular Sequence Data; D009154:Mutation; D011485:Protein Binding; D011487:Protein Conformation; D051736:Proto-Oncogene Proteins c-mdm2 / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000648:ultrastructure*
chemical_list: D016159:Tumor Suppressor Protein p53; D004247:DNA; D051736:Proto-Oncogene Proteins c-mdm2
keywords: Molecular dynamics simulation; Mutation; Small molecule inhibitor; Thermodynamic; p53