Thermodynamic Insights into the WT and Y220C TP53 DBDs Reveals that the Oncogenic Y220C Variant is a Loss of Function Mutation for Zn2+-binding at Physiological Temperature
Stuckey, J. I.; Vivat, V.; Dickson, B. M.; Setser, J. W.; Li, Y.; Cremers, C. M.; Wilson, J. E.; Peterle, D.; Engen, J. R.; Wales, T. E.; Wilcken, R.; Rohan, E. B.; Chenail, G.; Audia, J. E.; Sims, R. J.
Show abstract
We present evidence of previously unrecognized allosteric connectivity across the TP53 DNA binding domain (DBD). Specifically, we have found evidence of explicit influence on the Zn2+-binding site from the region surrounding the hotspot Y220C mutation. This allosteric connectivity is intertwined with a temperature-dependent destabilization of Zn2+ binding in both the WT and Y220C DBDs. Our studies indicate that the Y220C mutation exacerbates this temperature-dependent destabilization of Zn2+-binding to result in overall destabilization of the Y220C variant. We provide detailed thermodynamic evidence that Rezatapopt, a small molecule reactivator of the Y220C DBD, engages Y220C through two distinct thermodynamic pathways and restores WT-level Zn2+-affinity to this oncogenic variant. A series of thermodynamic models describing the WT and Y220C conformational landscapes, as well as the Rezatapopt binding mechanisms, are proposed.
Matching journals
The top 6 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Structure of human MUTYH and functional profiling of cancer-associated variants reveal an allosteric network between its cluster cofactor and active site required for DNA repair 96%
- Dynamic and structural insights into allosteric regulation on MKP5 a dual-specificity phosphatase 96%
- Structure of the catalytically active APOBEC3G bound to a DNA oligonucleotide inhibitor reveals tetrahedral geometry of the transition state 95%
Similar papers in this journal
- Protein and DNA Conformational Changes Contribute to Specificity of Cre Recombinase 95%
- Understanding ATP binding to DosS catalytic domain with a short ATP-lid 95%
- Oncogenic mutations in the DNA-binding domain of FOXO1 disrupt folding: quantitative insights from experiments and molecular simulations 95%
Similar papers in this journal
- Zinc shapes the folding landscape of p53 and establishes a new pathway for reactivating structurally diverse p53 mutants 97%
- Uncovering an allosteric mode of action for a selective inhibitor of human Bloom syndrome protein 95%
- Conformational dynamics and asymmetry in multimodal inhibition of membrane-bound pyrophosphatases 95%
Similar papers in this journal
- Evolution of an interaction between disordered proteins resulted in increased heterogeneity of the binding transition state 95%
- Role of substrate recognition in modulating strigolactone receptor selectivity in witchweed. 94%
- Biochemical characterization of Bacillus anthracis sortase B: Use in sortase mediated ligation and substrate recognition dependent on residues beyond the canonical pentapeptide binding motif for sortase enzymes 94%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.