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Updated: Feb 20, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
From mutational inactivation to aberrant gain-of-function: Unraveling the structural basis of mutant p53 oncogenic
Fisayo A Olotu1, Mahmoud E S Soliman1,2,3
1Molecular Modeling and Drug Design Research Group, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban, South Africa.
Abstract:
Various evidence has revealed that mutations in p53 exert activities that go beyond simply inactivation of wildtype functions but rather elicits downstream interactions that promote malignancy described as mutant p53 gain-of-function (GOF). Here we report the first account of the dynamics of mutation-induced structural transition of native p53 to an aberrant gain-of-function state, studying the wildtype (WT) and high incidence contact (R273C) and structural (R175H) mutant p53 (mutp53) through molecular dynamics simulation. Result analysis revealed that both mutants exhibited structural distortion and reduced flexibility, indicative of rigidity and kinetic stability. In addition, surface analysis revealed an increase in the accessible surface area in the p53 mutants. This suggests that the GOF transition involves protein unfolding and exposure of buried hydrophobic surface essential for interaction with HSF-1 oncogenic partner and wildtype p63, and p73 homologs. Further validation revealed binding cavities, similar in the mutants but dissimilar to the WT. Taken together, this study complements experimental findings and reveals the interplay between mutation-induced structural distortion, loss of flexibility, rigidity, enhanced stability, protein unfolding and ultimately, exposure of binding surfaces as conformational attributes that characterize mutP53 structure-GOF activities. This insight is, therefore, of great importance as it opens up a novel therapeutic approach toward the structure based targeting of mutP53 oncogenic involvement beyond wildtype inactivation. Furthermore, "exposed" binding site information obtained from this study can be explored for structure-based design of substances best described as "destabilizers" to disrupt the GOF interaction of mutp53.
Insights
Mutant p53 gain-of-function (GOF) involves structural changes beyond inactivation. This study reveals how mutations alter p53 structure, exposing binding sites crucial for cancer, offering new therapeutic targets.
Area of Science:
- Molecular Biology
- Structural Biology
- Oncology
Background:
- Mutations in the p53 gene can lead to a gain-of-function (GOF), promoting cancer beyond simple inactivation of its tumor-suppressive role.
- Understanding the structural dynamics of mutant p53 (mutp53) is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the dynamic structural transitions of wildtype (WT) p53 and common mutp53 variants (R273C, R175H) into a GOF state.
- To elucidate the conformational changes underlying mutp53 GOF activities and identify potential therapeutic targets.
Main Methods:
- Utilized molecular dynamics simulations to study the structural dynamics of WT p53, R273C mutp53, and R175H mutp53.
- Analyzed structural distortion, flexibility, accessible surface area, and binding cavities in both WT and mutant p53 forms.
Main Results:
- Mutant p53 forms exhibited structural distortion, reduced flexibility, increased rigidity, and enhanced kinetic stability compared to WT p53.
- Increased accessible surface area in mutants suggests protein unfolding, exposing hydrophobic surfaces for interactions with HSF-1, p63, and p73.
- Identified distinct binding cavities in mutants compared to WT p53, correlating with GOF interactions.
Conclusions:
- Mutation-induced structural changes, including unfolding and exposure of binding surfaces, are key to mutp53 GOF activities.
- These findings provide a structural basis for targeting mutp53's oncogenic functions, distinct from WT p53 inactivation.
- The identified exposed binding sites offer opportunities for structure-based drug design to disrupt mutp53 GOF interactions.
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