See detailed information on database contents in the users guide. Tp53 mutations, expression and interaction networks in. The p53 database was set up in 1991 and the first publication of the database in 1992 contained 300 mutations 5. We used default parameters in the pharmacophore module in discovery studio.
Metaanalysis of the p53 mutation database for mutant p53 biological activity. Software and program schrodingers maestro visualization program and accelrys discovery studio 4. The p53 mutations in cell lines compendium is a novel and original application that provides an id card for each cell line included in the umd tp53 database. The p53 binding site of mdm2 holds great promise as a target for therapeutic intervention in mdm2amplified p53 wildtype forms of cancer. Inactivation of p53 is the most prevalent defect in human cancers. To model the faknt p53 peptide interaction, the dock 6. This site still includes former features, such as tp53 history, tp53 information or the tp53 mutation database, but these features have been updated to take into account the most recent developments in this exciting field. This p53 family network displays interplays as it exhibits common. In recent years, there has been an exponential increase in the number of p53 mutations identified in human cancers. Identification of new inhibitors of mdm2p53 interaction. Staining of p53 and parp1 in breast cancer tmas and comparison with the tcga database indicated a higher doublepositive signal in basallike breast cancer than in luminal a or luminal b subtypes. The tumor suppressor protein p53 plays an important role in preventing tumor. The p53 mutation database consists of a list of point mutations in the p53 gene of human tumors and cell lines, compiled from the published literature and made available through electronic media.
Dual regulation of p53 by the ribosome maturation factor. Qsar models for isoindolinonebased p53 mdm2 interaction inhibitors using linear and nonlinear statistical methods xiaowu dong1, jingying yan1, dong lu1, peng wu1, jiadi gao1, tao liu1, bo. See how interaction crm software can optimize your firms marketing and business development strategy. The affinity of p53 for specific binding sites relative to other dna sequences is an. B p53, p63 and p73 interaction networks from interologous interaction database visualised with navigattor 2. The interaction of p53 and mdm2 genes in cancers, in silico studies and phylogenetic analysis jayaraman a1, jamil k1, raju s2 1school of biotechnology and bioinformatics, jawaharlal nehru. It includes a rigidbody structural comparison of target proteins to known templates of proteinprotein interfaces and a flexible refinement using a docking energy function. Please note that cellline data are also included in the dataset od somatic mutations. Algorithm for prediction of tumour suppressor p53 affinity. The new tp53 website has been launched with a novel design, updated information and improved readability.
A pathways database and viewer is being developed by bii scientists in collaboration with bind biomolecular interaction database, and will be available soon. Explaining oscillations and variability in the p53mdm2. Cartello,2 lisa cui, christophe beroud, and thierry soussi. The binding of p53 to sites that lack a p53 motif could result from a variety of factors, including p53 interactions. The umd tp53 variant database includes a full description of the 6,870 tp53 variants found in the database. For hierarchical clustering or to look at trends in the p53 chipseq data using the orio online resource for integrative omics platform. Revealing a human p53 universe nucleic acids research. The umd tp53 variant database includes a full description of the 6,870 tp53 variants found in the database with 70 novel features associated with each tp53 variant. The structures indicate how the substituents of a small molecule that bind to the three subpockets of the mdm2x p53 interaction. The tumour suppressor p53 is a transcription factor that binds dna in the vicinity of the genes it controls. As a member of the wwpdb, the rcsb pdb curates and annotates pdb data according to agreed upon standards. Higher parp1 protein levels and par proteins were detected in mtp53 r273h than in wildtype p53.
The structure viewer allows the user to view existing human p53. By using an approach similar to that of clinical metaanalyses, we clearly showed that several published studies have a p53 mutant activity profile that differs significantly from the normal distribution observed in other studies and can have a profound effect on the analysis of the p53 mutation database. Our current index contains 1,783,645 raw protein and genetic interactions from major model. An integrated in silico screening strategy for identifying. The interaction of p53 and mdm2 genes in cancers, in. The model with the highest scoring of fakntand p53 peptide interaction. Biogrid database of protein, chemical, and genetic. In contrast, unmodified ctd strengthens p53 interactions with cruciform targets. It is well known that stress induces an increase in levels of p53 which in turn leads to an increase in the transcription of mdm2.
The model of the p53 tetramer in interaction with a specific dna response element was built using the modeller software package 114 with the xray crystal structure 3kmd as a reference for the p53. Data tables and visualizations are interactive enabling scientists to look for novel patterns in the data. Dnabinding protects p53 from interactions with cofactors involved in transcriptionindependent functions. The nci database was further filtered with above models. Biogrid is an online interaction respository with data compiled through comprehensive curation efforts. Mutant p53 interactome identifies nardilysin as a p53r273h. Dnabinding protects p53 from interactions with cofactors. Lexisnexis keeps improving interaction and offers firms a great way to develop stronger relationships with clients, prospects and referral sources. Be aware that many cell lines may have different tp53 status according to different studies. The iarc tp53 database compiles various types of data and information on human tp53 gene variations related to cancer. Despite the extensive validation of this strategy, there are relatively few crystallographically determined cocomplex structures for smallmolecular inhibitors of the mdm2 p53 interaction. Mechanistically, ectopically expressed sbds triggered by, for example, ribosomal stress binds to the transactivation domain of p53 and perturbs the mdm2 p53 interaction, consequently. Since the 1997 release of the p53 database, a large number of changes have come about both in the database itself and in the software used to manage it 1,6,7.
Database protein sequence the protein sequences of p53 gene are showed in below table. Rapid identification of dual p53mdm2mdmx interaction. This application provides tools to mine, filter, and view p53 cistrome data in table format, and with hierarchical clustering of the filtered results. The umd tp53 mutation database includes the tp53 status of more than 80,400 tumors, individuals with germline mutations and cell lines. Structure based virtual screening, docking and molecular. Database and software for the analysis of mutations in the. Although the associations of p53 dysfunction, p53 interaction networks, and oncogenesis have been widely explored 5, a systematic analysis of tp53 mutations and the related interaction networks in various types of human cancers is lacking. The p53 tetramer shows an inducedfit interaction of the c. We employed prism 64,65 to screen 54 different potential interaction partners for the p53 dbd. Using a protein interaction chip approach, we first established the global tp53 and tp63 interaction network comprising of 383 and 301 proteins, respectively. We employed prism 64,65 to screen 54 different potential interaction partners for the p53. Thus, the study of the p53 pathway and its interaction networks is a promising source of insight for discovering therapeutic targets for tp53mutated cancers.
A p53 mutation database has been createdsee beroud et al. Prism is a motifbased software to predict proteinprotein interactions. Virtual screening for dual inhibitors of p53 mdm2mdmx interactions after filtering the nci database. Identification of new inhibitors of mdm2p53 interaction via pharmacophore and structurebased virtual screening. Modifications or deletion of the regulatory sequence in the ctd is required for p53 binding to target sites in bform dna. This site still includes former features, such as tp53 history, tp53 information or the tp53 mutation database. In addition, the structure of the recently reported spirooxindole inhibitor bound to mdm2 is described. Xray structures of mdm2 in complex with some ligands are available in protein data bank and herein, these data have been exploited to efficiently identify new p53mdm2 interaction antagonists through a hierarchical virtual screening strategy.