Reactivation of mutant p53: Constraints on mechanism highlighted by principal component analysis of the DNA binding domain.
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.
School of Chemistry, University of Southampton, Southampton, SO17 1BJ, United Kingdom.|Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, 138671, Singapore.
Zahra
Z
Ouaray
York Centre for Complex Systems Analysis (YCCSA), University of York, York, YO10 5GE, United Kingdom.|Department of Chemistry, College of Science, Qassim University, Buraydah, 52571, Saudi Arabia.
Karim M
KM
ElSawy
p53 Laboratory, Agency for Science, Technology and Research, Singapore, 138648, Singapore.
David P
DP
Lane
School of Chemistry, University of Southampton, Southampton, SO17 1BJ, United Kingdom. J.W.Essex@soton.ac.uk.
Jonathan W
JW
Essex
Bioinformatics Institute, Agency for Science, Technology and Research, Singapore, 138671, Singapore.|School of Biological Sciences, Nanyang Technological University, 637551, Singapore.|Department of Biological Sciences, National University of Singapore, 117543, Singapore.
Chandra
C
Verma
D000595:Amino Acid Sequence; D001059:Apoproteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D001665:Binding Sites; D017124:Conserved Sequence; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006801:Humans; D008958:Models, Molecular; D018583:Pliability; D025341:Principal Component Analysis; D011485:Protein Binding; D000072417:Protein Domains; D055503:Protein Multimerization; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D013329:Structure-Activity Relationship; D016159:Tumor Suppressor Protein p53 / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism
D001059:Apoproteins; D016159:Tumor Suppressor Protein p53; D004247:DNA
DNA; flexibility; induced fit; p53 DNA binding domain; principal component analysis; specificity