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Structure and Function of p53-DNA Complexes with Inactivation and Rescue Mutations: A Molecular Dynamics Simulation Study.

Kamaraj B, Bogaerts A - PLoS ONE (2015)

Bottom Line: The tumor suppressor protein p53 can lose its function upon DNA-contact mutations (R273C and R273H) in the core DNA-binding domain.The activity can be restored by second-site suppressor or rescue mutations (R273C_T284R, R273H_T284R, and R273H_S240R).This study clearly illustrates that, due to DNA-contact mutants, the p53 structure loses its stability and becomes more rigid than the native protein.

View Article: PubMed Central - PubMed

Affiliation: Research group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk-Antwerp, Belgium.

ABSTRACT
The tumor suppressor protein p53 can lose its function upon DNA-contact mutations (R273C and R273H) in the core DNA-binding domain. The activity can be restored by second-site suppressor or rescue mutations (R273C_T284R, R273H_T284R, and R273H_S240R). In this paper, we elucidate the structural and functional consequence of p53 proteins upon DNA-contact mutations and rescue mutations and the underlying mechanisms at the atomic level by means of molecular dynamics simulations. Furthermore, we also apply the docking approach to investigate the binding phenomena between the p53 protein and DNA upon DNA-contact mutations and rescue mutations. This study clearly illustrates that, due to DNA-contact mutants, the p53 structure loses its stability and becomes more rigid than the native protein. This structural loss might affect the p53-DNA interaction and leads to inhibition of the cancer suppression. Rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) can restore the functional activity of the p53 protein upon DNA-contact mutations and show a good interaction between the p53 protein and a DNA molecule, which may lead to reactivate the cancer suppression function. Understanding the effects of p53 cancer and rescue mutations at the molecular level will be helpful for designing drugs for p53 associated cancer diseases. These drugs should be designed so that they can help to inhibit the abnormal function of the p53 protein and to reactivate the p53 function (cell apoptosis) to treat human cancer.

No MeSH data available.


Related in: MedlinePlus

RMSF of the backbone of C-alpha atoms of native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus residue at 300K.(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.
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pone.0134638.g003: RMSF of the backbone of C-alpha atoms of native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus residue at 300K.(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.

Mentions: To determine the dynamic behaviour of the p53 protein residues upon DNA-contact (R273C and R273H) and rescue mutations (R273C_T284R, R273H_T284R and R273H_S240R), the RMSF of native, DNA-contact and rescue mutant structures are depicted in Fig 3A–3C. The DNA-contact mutations (R273C and R273H) show a lower degree of flexibility than native p53, whereas the rescue mutations (R273C_T284R, R273H_T284R and R273H_S240R) show a similar flexibility as native p53 throughout the simulation time. This further illustrates that the DNA-contact mutants lose the flexible conformation and become more rigid whereas the rescue mutants can restore the flexible conformation in the p53 protein.


Structure and Function of p53-DNA Complexes with Inactivation and Rescue Mutations: A Molecular Dynamics Simulation Study.

Kamaraj B, Bogaerts A - PLoS ONE (2015)

RMSF of the backbone of C-alpha atoms of native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus residue at 300K.(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4526489&req=5

pone.0134638.g003: RMSF of the backbone of C-alpha atoms of native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus residue at 300K.(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.
Mentions: To determine the dynamic behaviour of the p53 protein residues upon DNA-contact (R273C and R273H) and rescue mutations (R273C_T284R, R273H_T284R and R273H_S240R), the RMSF of native, DNA-contact and rescue mutant structures are depicted in Fig 3A–3C. The DNA-contact mutations (R273C and R273H) show a lower degree of flexibility than native p53, whereas the rescue mutations (R273C_T284R, R273H_T284R and R273H_S240R) show a similar flexibility as native p53 throughout the simulation time. This further illustrates that the DNA-contact mutants lose the flexible conformation and become more rigid whereas the rescue mutants can restore the flexible conformation in the p53 protein.

Bottom Line: The tumor suppressor protein p53 can lose its function upon DNA-contact mutations (R273C and R273H) in the core DNA-binding domain.The activity can be restored by second-site suppressor or rescue mutations (R273C_T284R, R273H_T284R, and R273H_S240R).This study clearly illustrates that, due to DNA-contact mutants, the p53 structure loses its stability and becomes more rigid than the native protein.

View Article: PubMed Central - PubMed

Affiliation: Research group PLASMANT, Department of Chemistry, University of Antwerp, Universiteitsplein 1, 2610, Wilrijk-Antwerp, Belgium.

ABSTRACT
The tumor suppressor protein p53 can lose its function upon DNA-contact mutations (R273C and R273H) in the core DNA-binding domain. The activity can be restored by second-site suppressor or rescue mutations (R273C_T284R, R273H_T284R, and R273H_S240R). In this paper, we elucidate the structural and functional consequence of p53 proteins upon DNA-contact mutations and rescue mutations and the underlying mechanisms at the atomic level by means of molecular dynamics simulations. Furthermore, we also apply the docking approach to investigate the binding phenomena between the p53 protein and DNA upon DNA-contact mutations and rescue mutations. This study clearly illustrates that, due to DNA-contact mutants, the p53 structure loses its stability and becomes more rigid than the native protein. This structural loss might affect the p53-DNA interaction and leads to inhibition of the cancer suppression. Rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) can restore the functional activity of the p53 protein upon DNA-contact mutations and show a good interaction between the p53 protein and a DNA molecule, which may lead to reactivate the cancer suppression function. Understanding the effects of p53 cancer and rescue mutations at the molecular level will be helpful for designing drugs for p53 associated cancer diseases. These drugs should be designed so that they can help to inhibit the abnormal function of the p53 protein and to reactivate the p53 function (cell apoptosis) to treat human cancer.

No MeSH data available.


Related in: MedlinePlus