Next Article in Journal
Transcriptional Responses of Creeping Bentgrass to 2,3-Butanediol, a Bacterial Volatile Compound (BVC) Analogue
Next Article in Special Issue
Rapid Screening of Active Components with an Osteoclastic Inhibitory Effect in Herba epimedii Using Quantitative Pattern–Activity Relationships Based on Joint-Action Models
Previous Article in Journal
Lactose Binding Induces Opposing Dynamics Changes in Human Galectins Revealed by NMR-Based Hydrogen–Deuterium Exchange
Previous Article in Special Issue
Metal Atom Effect on the Photophysical Properties of Mg(II), Zn(II), Cd(II), and Pd(II) Tetraphenylporphyrin Complexes Proposed as Possible Drugs in Photodynamic Therapy
Article Menu
Issue 8 (August) cover image

Export Article

Open AccessArticle
Molecules 2017, 22(8), 1358; doi:10.3390/molecules22081358

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

1
Department of Mechanical and Aerospace Engineering, Politecnico di Torino, 10129 Torino, Italy
2
Department of Oncology, University of Alberta, Edmonton, AB T6G 2R3, Canada
3
Istituto Dalle Molle di studi sull’Intelligenza Artificiale (IDSIA), Scuola universitaria professionale della Svizzera italiana (SUPSI), Università della Svizzera italiana (USI), Centro Galleria 2, CH-6928 Manno, Switzerland
4
Department of Oncology, Department of Physics, University of Alberta, Edmonton, AB T6G 2R3, Canada
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Received: 2 August 2017 / Revised: 13 August 2017 / Accepted: 13 August 2017 / Published: 16 August 2017
(This article belongs to the Special Issue Frontiers in Computational Chemistry for Drug Discovery)
View Full-Text   |   Download PDF [2800 KB, uploaded 16 August 2017]   |  

Abstract

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. View Full-Text
Keywords: p53; G245S-mp53; MD simulations; functional mode analysis p53; G245S-mp53; MD simulations; functional mode analysis
Figures

Figure 1

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

Supplementary material

Scifeed alert for new publications

Never miss any articles matching your research from any publisher
  • Get alerts for new papers matching your research
  • Find out the new papers from selected authors
  • Updated daily for 49'000+ journals and 6000+ publishers
  • Define your Scifeed now

SciFeed Share & Cite This Article

MDPI and ACS Style

Lepre, M.G.; Omar, S.I.; Grasso, G.; Morbiducci, U.; Deriu, M.A.; Tuszynski, J.A. Insights into the Effect of the G245S Single Point Mutation on the Structure of p53 and the Binding of the Protein to DNA. Molecules 2017, 22, 1358.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]

Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top