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Simulating the role of conformational stabilization in p53 and its effect on oncogenesis

Simulating the role of conformational stabilization in p53 and its effect on oncogenesis
Simulating the role of conformational stabilization in p53 and its effect on oncogenesis
The p53 tumour suppressor protein functions as a transcription factor to prevent cancer by inducing cell cycle arrest, DNA repair and apoptosis. 50% of cancers are associated with a mutation on this protein; indeed mutated p53 either loses its capacity to bind DNA or is destabilised which induces the proliferation of DNA-damaged cells. 95% of these mutations occur on the p53 DNA-binding domain (DBD). In the present study, the use of computational methods and structural analysis allowed us to investigate p53DBD dynamics at an atomistic level. Principal component analysis of p53DBD experimental structures (NMR and Xray), as well as of the DNA sequences to which these were bound, confirmed the role of the tetramerisation domain in p53 DNA binding specificity and contradicted the belief that the DNA-bound p53DBD and the apo p53DBD can present similar conformations. Conventional and accelerated molecular dynamics (cMD and aMD) were used to investigate the role of p53DBD cysteine alkylation by Michael acceptors (MAs) and the destabilisation of a p53DBD temperature sensitive mutant (V143A). Both techniques highlighted a stable p53DBD dimerization interface (H1 ?-helix) as being implicated in the mutant rescue process. While further investigations are needed to confirm our conclusions, these early results might help to design more specific anti-cancer drugs.
Ouaray, Zahra
1e9b5915-30d7-4dad-ba2f-13655ff2093c
Ouaray, Zahra
1e9b5915-30d7-4dad-ba2f-13655ff2093c
Essex, Jonathan
1f409cfe-6ba4-42e2-a0ab-a931826314b5

(2015) Simulating the role of conformational stabilization in p53 and its effect on oncogenesis. University of Southampton, Chemistry, Doctoral Thesis, 260pp.

Record type: Thesis (Doctoral)

Abstract

The p53 tumour suppressor protein functions as a transcription factor to prevent cancer by inducing cell cycle arrest, DNA repair and apoptosis. 50% of cancers are associated with a mutation on this protein; indeed mutated p53 either loses its capacity to bind DNA or is destabilised which induces the proliferation of DNA-damaged cells. 95% of these mutations occur on the p53 DNA-binding domain (DBD). In the present study, the use of computational methods and structural analysis allowed us to investigate p53DBD dynamics at an atomistic level. Principal component analysis of p53DBD experimental structures (NMR and Xray), as well as of the DNA sequences to which these were bound, confirmed the role of the tetramerisation domain in p53 DNA binding specificity and contradicted the belief that the DNA-bound p53DBD and the apo p53DBD can present similar conformations. Conventional and accelerated molecular dynamics (cMD and aMD) were used to investigate the role of p53DBD cysteine alkylation by Michael acceptors (MAs) and the destabilisation of a p53DBD temperature sensitive mutant (V143A). Both techniques highlighted a stable p53DBD dimerization interface (H1 ?-helix) as being implicated in the mutant rescue process. While further investigations are needed to confirm our conclusions, these early results might help to design more specific anti-cancer drugs.

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Published date: 25 June 2015
Organisations: University of Southampton, Chemistry

Identifiers

Local EPrints ID: 380906
URI: http://eprints.soton.ac.uk/id/eprint/380906
PURE UUID: 08e13c04-80b9-4ccc-be99-43a9b473f3a1
ORCID for Jonathan Essex: ORCID iD orcid.org/0000-0003-2639-2746

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Date deposited: 22 Sep 2015 12:48
Last modified: 25 Jun 2018 04:01

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