ArticleProteins2013
Impact of the K24N mutation on the transactivation domain of p53 and its binding to murine double-minute clone 2.
Article in Proteins, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed.
- Re-Balancing Replica Exchange with Solute Tempering for Sampling Dynamic Protein Conformations.Journal of chemical theory and computation · 2023Article
- Synthesis of Amino Acids Bearing Halodifluoromethyl Moieties and Their Application to p53-Derived Peptides Binding to Mdm2/Mdm4.Drug design, development and therapy · 2023Article
- Toward Accurate Coarse-Grained Simulations of Disordered Proteins and Their Dynamic Interactions.Journal of chemical information and modeling · 2022Article
- The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer.Molecular biology and evolution · 2022Article
- Cancer-Associated Mutations Perturb the Disordered Ensemble and Interactions of the Intrinsically Disordered p53 Transactivation Domain.Journal of molecular biology · 2021Article
- Implementation of adaptive integration method for free energy calculations in molecular systems.PeerJ. Computer science · 2020Article
- Modulation of p53 Transactivation Domain Conformations by Ligand Binding and Cancer-Associated Mutations.Pacific Symposium on Biocomputing. Pacific Symposium on Biocomputing · 2020Article
- Sequence specificity despite intrinsic disorder: How a disease-associated Val/Met polymorphism rearranges tertiary interactions in a long disordered protein.PLoS computational biology · 2019Article
- Residual Structures and Transient Long-Range Interactions of p53 Transactivation Domain: Assessment of Explicit Solvent Protein Force Fields.Journal of chemical theory and computation · 2019Article
- Parallel Mutations Result in a Wide Range of Cooperation and Community Consequences in a Two-Species Bacterial Consortium.PloS one · 2016Article
- The cis conformation of proline leads to weaker binding of a p53 peptide to MDM2 compared to trans.Archives of biochemistry and biophysics · 2015Article
- Modulation of the disordered conformational ensembles of the p53 transactivation domain by cancer-associated mutations.PLoS computational biology · 2015Article
- Transcriptional Activation of p53 during Cold Induced Torpor in the 13-Lined Ground Squirrel Ictidomys tridecemlineatus.Biochemistry research international · 2015Article
- Digested disorder, Quarterly intrinsic disorder digest (October-November-December, 2013).Intrinsically disordered proteins · 2015Article
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Authors and funding
5 authors.
Funding
Abstract
The level of the p53 transcription factor is negatively regulated by the E3 ubiquitin ligase murine double-minute clone 2 (MDM2). The interaction between p53 and MDM2 is essential for the maintenance of genomic integrity for most eukaryotes. Previous structural studies revealed that MDM2 binds to p53 transactivation domain (p53TAD) from residues 17 to 29. The K24N mutation of p53TAD changes a lysine at position 24 to an asparagine. This mutation occurs naturally in the bovine family and is also found in a rare form of human gestational cancer called choriocarcinoma. In this study, we have investigated how the K24N mutation affects the affinity, structure, and dynamics of p53TAD binding to MDM2. Nuclear magnetic resonance studies of p53TAD show that the K24N mutant is more flexible and has less transient helical secondary structure than the wild type. Isothermal titration calorimetry measurements demonstrate that these changes in structure and dynamics do not significantly change the binding affinity for p53TAD-MDM2. Finally, free-energy perturbation and standard molecular dynamic simulations suggest the negligible affinity change is due to a compensating interaction energy between the K24N mutant and the MDM2 when it is bound. Overall, the data suggest that the K24N-MDM2 complex is able to, at least partly, compensate for an increase in the conformational entropy in unbound K24N with an increase in the bound-state electrostatic interaction energy.
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