Reactivation of mutant p53: Constraints on mechanism highlighted by principal component analysis of the DNA binding domain |
| |
Authors: | Zahra Ouaray Karim M. ElSawy David P. Lane Jonathan W. Essex Chandra Verma |
| |
Affiliation: | 1. School of Chemistry, University of Southampton, Southampton, United Kingdom;2. Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, Singapore;3. York Centre for Complex Systems Analysis (YCCSA), University of York, York, United Kingdom;4. Department of Chemistry, College of Science, Qassim University, Buraydah, Saudi Arabia;5. p53 Laboratory, Agency for Science, Technology and Research, Singapore, Singapore;6. School of Biological Sciences, Nanyang Technological University, Singapore;7. Department of Biological Sciences, National University of Singapore, Singapore |
| |
Abstract: | Most p53 mutations associated with cancer are located in its DNA binding domain (DBD). Many structures (X‐ray and NMR) of this domain are available in the protein data bank (PDB) and a vast conformational heterogeneity characterizes the various free and complexed states. The major difference between the apo and the holo‐complexed states appears to lie in the L1 loop. In particular, the conformations of this loop appear to depend intimately on the sequence of DNA to which it binds. This conclusion builds upon recent observations that implicate the tetramerization and the C‐terminal domains (respectively TD and Cter) in DNA binding specificity. Detailed PCA analysis of the most recent collection of DBD structures from the PDB have been carried out. In contrast to recommendations that small molecules/drugs stabilize the flexible L1 loop to rescue mutant p53, our study highlights a need to retain the flexibility of the p53 DNA binding surface (DBS). It is the adaptability of this region that enables p53 to engage in the diverse interactions responsible for its functionality. Proteins 2016; 84:1443–1461. © 2016 Wiley Periodicals, Inc. |
| |
Keywords: | principal component analysis p53 DNA binding domain DNA induced fit flexibility specificity |
|
|