Limits...
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

Average number of intermolecular hydrogen bonds in native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus time 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

License
getmorefigures.php?uid=PMC4526489&req=5

pone.0134638.g006: Average number of intermolecular hydrogen bonds in native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus time at 300K.(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.

Mentions: We also observed notable differences in the NH-bond pattern during the simulation. The hydrogen bonds account for a major factor of maintaining the stable conformation of the protein. NH-bond analysis of native and DNA-contact and rescue mutations of the p53 proteins was performed with respect to time in order to understand the relationship between flexibility and hydrogen bond formation. The DNA-contact mutants (R273C and R273H) show a slightly larger number of NH-bonds formed during the simulation than the native p53 protein (see Fig 6A–6C). The rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) show less NH-bonds than the DNA-contact mutants and show almost a similar number of H-bonds as the native p53 protein. The average number of NH-bonds is given in S1 Table. The NH bond results of the native, DNA-contact and rescue mutant structures correlate well with the RMSD, RMSF, Rg and SASA plot results. The results indicate that the p53 protein conformation becomes more rigid in nature upon DNA-contact mutants (R273C and R273H), which affects the functional behaviour of the p53 protein. On the other hand, the second site suppressor or rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) alter the structural disturbance of the p53 protein upon DNA-contact mutants, and can thus rescue the structural and functional behaviour of 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)

Average number of intermolecular hydrogen bonds in native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus time 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

License
Show All Figures
getmorefigures.php?uid=PMC4526489&req=5

pone.0134638.g006: Average number of intermolecular hydrogen bonds in native, DNA-contact (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) of the p53 protein versus time at 300K.(a) Native, R273C and R273C_T284R, (b) Native, R273H and R273H_T284R, (c) Native, R273H and R273H_S240R.
Mentions: We also observed notable differences in the NH-bond pattern during the simulation. The hydrogen bonds account for a major factor of maintaining the stable conformation of the protein. NH-bond analysis of native and DNA-contact and rescue mutations of the p53 proteins was performed with respect to time in order to understand the relationship between flexibility and hydrogen bond formation. The DNA-contact mutants (R273C and R273H) show a slightly larger number of NH-bonds formed during the simulation than the native p53 protein (see Fig 6A–6C). The rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) show less NH-bonds than the DNA-contact mutants and show almost a similar number of H-bonds as the native p53 protein. The average number of NH-bonds is given in S1 Table. The NH bond results of the native, DNA-contact and rescue mutant structures correlate well with the RMSD, RMSF, Rg and SASA plot results. The results indicate that the p53 protein conformation becomes more rigid in nature upon DNA-contact mutants (R273C and R273H), which affects the functional behaviour of the p53 protein. On the other hand, the second site suppressor or rescue mutants (R273C_T284R, R273H_T284R and R273H_S240R) alter the structural disturbance of the p53 protein upon DNA-contact mutants, and can thus rescue the structural and functional behaviour of 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