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Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA

The transcription factor p53 is a potent tumor suppressor dubbed as the “guardian of the genome” because of its ability to orchestrate protective biological outputs in response to a variety of oncogenic stresses. Mutation and thus inactivation of p53 can be found in 50% of human tumors. The majority...

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Autores principales: Lepre, Marco Gaetano, Omar, Sara Ibrahim, Grasso, Gianvito, Morbiducci, Umberto, Deriu, Marco Agostino, Tuszynski, Jack A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152093/
https://www.ncbi.nlm.nih.gov/pubmed/28813011
http://dx.doi.org/10.3390/molecules22081358
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author Lepre, Marco Gaetano
Omar, Sara Ibrahim
Grasso, Gianvito
Morbiducci, Umberto
Deriu, Marco Agostino
Tuszynski, Jack A.
author_facet Lepre, Marco Gaetano
Omar, Sara Ibrahim
Grasso, Gianvito
Morbiducci, Umberto
Deriu, Marco Agostino
Tuszynski, Jack A.
author_sort Lepre, Marco Gaetano
collection PubMed
description The transcription factor p53 is a potent tumor suppressor dubbed as the “guardian of the genome” because of its ability to orchestrate protective biological outputs in response to a variety of oncogenic stresses. Mutation and thus inactivation of p53 can be found in 50% of human tumors. The majority are missense mutations located in the DNA binding region. Among them, G245S is known to be a structural hotspot mutation. To understand the behaviors and differences between the wild-type and mutant, both a dimer of the wild type p53 (wt-p53) and its G245S mutant (G245S-mp53), complexed with DNA, were simulated using molecular dynamics for more than 1 μs. wt-p53 and G245S-mp53 apo monomers were simulated for 1 μs as well. Conformational analyses and binding energy evaluations performed underline important differences and therefore provide insights to understand the G245S-mp53 loss of function. Our results indicate that the G245S mutation destabilizes several structural regions in the protein that are crucial for DNA binding when found in its apo form and highlight differences in the mutant-DNA complex structure compared to the wt protein. These findings not only provide means that can be applied to other p53 mutants but also serve as structural basis for further studies aimed at the development of cancer therapies based on restoring the function of p53.
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spelling pubmed-61520932018-11-13 Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA Lepre, Marco Gaetano Omar, Sara Ibrahim Grasso, Gianvito Morbiducci, Umberto Deriu, Marco Agostino Tuszynski, Jack A. Molecules Article The transcription factor p53 is a potent tumor suppressor dubbed as the “guardian of the genome” because of its ability to orchestrate protective biological outputs in response to a variety of oncogenic stresses. Mutation and thus inactivation of p53 can be found in 50% of human tumors. The majority are missense mutations located in the DNA binding region. Among them, G245S is known to be a structural hotspot mutation. To understand the behaviors and differences between the wild-type and mutant, both a dimer of the wild type p53 (wt-p53) and its G245S mutant (G245S-mp53), complexed with DNA, were simulated using molecular dynamics for more than 1 μs. wt-p53 and G245S-mp53 apo monomers were simulated for 1 μs as well. Conformational analyses and binding energy evaluations performed underline important differences and therefore provide insights to understand the G245S-mp53 loss of function. Our results indicate that the G245S mutation destabilizes several structural regions in the protein that are crucial for DNA binding when found in its apo form and highlight differences in the mutant-DNA complex structure compared to the wt protein. These findings not only provide means that can be applied to other p53 mutants but also serve as structural basis for further studies aimed at the development of cancer therapies based on restoring the function of p53. MDPI 2017-08-16 /pmc/articles/PMC6152093/ /pubmed/28813011 http://dx.doi.org/10.3390/molecules22081358 Text en © 2017 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Lepre, Marco Gaetano
Omar, Sara Ibrahim
Grasso, Gianvito
Morbiducci, Umberto
Deriu, Marco Agostino
Tuszynski, Jack A.
Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA
title Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA
title_full Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA
title_fullStr Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA
title_full_unstemmed Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA
title_short Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA
title_sort insights into the effect of the g245s single point mutation on the structure of p53 and the binding of the protein to dna
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6152093/
https://www.ncbi.nlm.nih.gov/pubmed/28813011
http://dx.doi.org/10.3390/molecules22081358
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