Dynamic perspectives into the mechanisms of mutation-induced p53-DNA binding loss and inactivation using active perturbation theory: Structural and molecular insights toward the design of potent reactivators in cancer therapy

Journal of Cellular Biochemistry
Fisayo A Olotu, Mahmoud E S Soliman

Abstract

The DNA-binding ability of p53 represents the crux of its tumor suppressive activities, which involves transcriptional activation of target genes responsible for apoptosis and cell-cycle arrest. Mutational occurrences within or in close proximity to the DNA-binding surface of p53 have accounted for the loss of direct DNA-binding ability and inactivation implicated in many cases of cancer. Moreover, the design of therapeutic compounds that can restore DNA-binding ability in p53 mutants has been identified as a way forward in curtailing their oncogenic activities. However, there is still the need for more insights into evaluate the perturbations that occur at the DNA-binding interface of mp53 relative to DNA-binding loss, inactivation, and design of potent reactivators, hence the purpose of this study. Therefore, we evaluated p53-structural (R175H) and contact (R273C) mutational effects using tunnel perturbation analysis and other computational tools. We identified significant perturbations in the active tunnels of p53, which resulted in altered geometry and loss, unlike in the wild-type p53. This corroborated with structural, DNA-binding, and interaction network analysis, which showed that loss of flexibility, repulsion of DNA-i...Continue Reading

References

Apr 1, 1992·Nature Genetics·W S el-DeiryB Vogelstein
Jun 1, 1992·Molecular and Cellular Biology·W D FunkJ W Shay
May 20, 1994·Journal of Molecular Biology·I K McDonald, J M Thornton
May 1, 1996·Genes & Development·L J Ko, C Prives
Sep 7, 2000·Leukemia & Lymphoma·M B Møller
Dec 1, 2000·Nature·B VogelsteinA J Levine
May 17, 2001·Proceedings of the National Academy of Sciences of the United States of America·T M RaschkeM Levitt
Apr 18, 2002·Proceedings of the National Academy of Sciences of the United States of America·Peter J WinnRebecca C Wade
May 15, 2002·Human Mutation·Magali OlivierPierre Hainaut
Aug 3, 2002·Nature Reviews. Cancer·Karen H Vousden, Xin Lu
Aug 7, 2002·Current Opinion in Structural Biology·Roland L Dunbrack
Feb 13, 2003·Journal of the American Chemical Society·Cyril DominguezAlexandre M J J Bonvin
Mar 6, 2003·Human Mutation·Christophe Béroud, Thierry Soussi
Apr 30, 2003·Cell Death and Differentiation·Yang Xu
Jun 5, 2003·Proteins·Joël JaninUNKNOWN Critical Assessment of PRedicted Interactions
Jan 28, 2004·Cell·Charles J Sherr
Jul 21, 2004·Journal of Computational Chemistry·Eric F PettersenThomas E Ferrin
Oct 4, 2005·Journal of Computational Chemistry·David A CaseRobert J Woods
Jun 24, 2006·BMC Bioinformatics·Martin PetrekJirí Damborský
Jun 24, 2006·Molecular Cell·Malka KitaynerZippora Shakked
Oct 4, 2006·Proceedings of the National Academy of Sciences of the United States of America·Andreas C JoergerAlan R Fersht
Mar 6, 2007·Journal of Molecular Biology·Shude YanShohei Koide
Apr 23, 2008·Current Protocols in Bioinformatics·Narayanan EswarAndrej Sali
Oct 17, 2008·Molekuliarnaia biologiia·M Iu LobanovO V Galzitskaia
Nov 15, 2008·Biochimica Et Biophysica Acta·Angelina V Vaseva, Ute M Moll
Feb 26, 2010·Cold Spring Harbor Perspectives in Biology·Magali OlivierPierre Hainaut
Mar 26, 2010·Annual Review of Biochemistry·Remo RohsRichard S Mann
May 1, 2010·Nature Protocols·Sjoerd J de VriesAlexandre M J J Bonvin
May 12, 2010·Cold Spring Harbor Perspectives in Biology·David W Meek, Carl W Anderson
May 14, 2010·Cold Spring Harbor Perspectives in Biology·David Lane, Arnold Levine
Oct 12, 2010·Trends in Molecular Medicine·Chao Dai, Wei Gu
Feb 3, 2011·Proteins·Aurélie BornotAlexandre G de Brevern
Feb 25, 2011·Trends in Biochemical Sciences·Nadezhda T DonchevaMario Albrecht
May 19, 2012·International Journal of Biological Sciences·Bo Gu, Wei-Guo Zhu

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Citations

Jan 26, 2020·Computational Biology and Chemistry·Elliasu Y SalifuMahmoud E S Soliman
Oct 16, 2020·Cell Biochemistry and Biophysics·Kehinde F OmolabiMahmoud E S Soliman
Apr 10, 2021·Frontiers in Cell and Developmental Biology·Qi YuStephanie K Seidlits
Aug 14, 2021·Oncology Letters·Xiaohan KongSijie Li

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