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

Residue interaction at the protein-DNA interface in the p53-DNA complex.(a) Native-DNA complex, (b) R273C-DNA complex, (c) R273H-DNA complex, (d) R273C_T284R-DNA complex, (e) R273H_T284R-DNA complex and (f) R273H_S240R-DNA complex. The color coding represents the p53 protein in brown color, DNA in purple color. Hydrogen bonding interactions are denoted by dashed lines. This figure was prepared by Ligplot.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134638.g008: Residue interaction at the protein-DNA interface in the p53-DNA complex.(a) Native-DNA complex, (b) R273C-DNA complex, (c) R273H-DNA complex, (d) R273C_T284R-DNA complex, (e) R273H_T284R-DNA complex and (f) R273H_S240R-DNA complex. The color coding represents the p53 protein in brown color, DNA in purple color. Hydrogen bonding interactions are denoted by dashed lines. This figure was prepared by Ligplot.

Mentions: The number of intermolecular hydrogen bonds was therefore calculated for the native, DNA-contact mutants (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273C-S240R) of the p53-DNA complexes, and the values are listed in S4 Table. The native-DNA complex shows a total of 16 hydrogen bonds between the biomolecules. Arg280, Lys120, Ser241, Asn239, Met243, Cys242, His179, Cys176, Asp184, Asn235, Asp186, Tyr205, Lys182 and His178 act as essential binding site residues in the native-DNA complex (indicated with green dashed lines in Fig 8A). Both DNA-contact mutants (R273C and R273H) of the p53-DNA complexes show only 6 hydrogen bonds (see Fig 8B and 8C). This clearly confirms that the lower number of hydrogen bonds reduces its affinity and also results in the alteration in the binding pattern between the p53 and DNA molecule. The rescue mutants (R273C_T284R, R273H_T284R and R273C-S240R) of the p53-DNA complexes, on the other hand, show 16, 18 and 21 hydrogen bonds, respectively, and they exhibit a similar binding pattern and good affinity with the DNA molecule (Fig 8D–8F).


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

Kamaraj B, Bogaerts A - PLoS ONE (2015)

Residue interaction at the protein-DNA interface in the p53-DNA complex.(a) Native-DNA complex, (b) R273C-DNA complex, (c) R273H-DNA complex, (d) R273C_T284R-DNA complex, (e) R273H_T284R-DNA complex and (f) R273H_S240R-DNA complex. The color coding represents the p53 protein in brown color, DNA in purple color. Hydrogen bonding interactions are denoted by dashed lines. This figure was prepared by Ligplot.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0134638.g008: Residue interaction at the protein-DNA interface in the p53-DNA complex.(a) Native-DNA complex, (b) R273C-DNA complex, (c) R273H-DNA complex, (d) R273C_T284R-DNA complex, (e) R273H_T284R-DNA complex and (f) R273H_S240R-DNA complex. The color coding represents the p53 protein in brown color, DNA in purple color. Hydrogen bonding interactions are denoted by dashed lines. This figure was prepared by Ligplot.
Mentions: The number of intermolecular hydrogen bonds was therefore calculated for the native, DNA-contact mutants (R273C and R273H) and rescue mutants (R273C_T284R, R273H_T284R and R273C-S240R) of the p53-DNA complexes, and the values are listed in S4 Table. The native-DNA complex shows a total of 16 hydrogen bonds between the biomolecules. Arg280, Lys120, Ser241, Asn239, Met243, Cys242, His179, Cys176, Asp184, Asn235, Asp186, Tyr205, Lys182 and His178 act as essential binding site residues in the native-DNA complex (indicated with green dashed lines in Fig 8A). Both DNA-contact mutants (R273C and R273H) of the p53-DNA complexes show only 6 hydrogen bonds (see Fig 8B and 8C). This clearly confirms that the lower number of hydrogen bonds reduces its affinity and also results in the alteration in the binding pattern between the p53 and DNA molecule. The rescue mutants (R273C_T284R, R273H_T284R and R273C-S240R) of the p53-DNA complexes, on the other hand, show 16, 18 and 21 hydrogen bonds, respectively, and they exhibit a similar binding pattern and good affinity with the DNA molecule (Fig 8D–8F).

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