Structural Basis of DNA Recognition by p53 Tetramers

Kitayner, M.; Rozenberg, Haim; Kessler, Naama; Rabinovich, D.; Shaulov, Lihi; Haran, Tali E.; Shakked, Zippora

doi:10.1016/j.molcel.2006.05.015

Cited by 366 publications

(619 citation statements)

References 59 publications

(73 reference statements)

Supporting

Mentioning

582

Contrasting

Unclassified

Order By: Relevance

“…Studies of the structural properties could present significant difficulties for structural biologists. However, with the accumulating experimental structural results 19,20,49 and with more advanced computational power, computational studies can play a more important role in revealing the relationship between the complex structure and transcriptional selection and activity.…”

Section: Resultsmentioning

confidence: 99%

“…The role of the specific interaction of Lys120 with DNA is unclear because of its variable presence in existing crystal structures. Lys120 was attached to the mobile loop L1 of the p53 protein and it is likely that because of this flexible structural feature, the Lys120-DNA interactions were well maintained in some crystal structures under one condition 11 , while in others these interactions were not observed 19,20 . Arg248, on the other hand, interacts with the DNA backbone and therefore was less specific in its interactions with the DNA, and these interactions were relatively better maintained in all of the complexes in our simulations.…”

Section: Analysis Of the P53-dna And The P53-p53 Interactionsmentioning

confidence: 99%

“…Several structures involving p53 core domain-DNA specific binding became available during the last decade 11,[18][19][20] . Biophysical and biochemical data 11,[21][22][23][24] were obtained and a similar p53 core domain tetramer-DNA complex model was proposed 11,[21][22][23][24] .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Pan

Nussinov

2008

J. Phys. Chem. B

View full text Add to dashboard Cite

Specific p53 binding-induced DNA bending and its underlying driving forces are crucial for the understanding of selective transcription activation. Diverse p53-response elements exist in the genome. However, it is not known what determines the DNA bending and to what extent. In order to gain knowledge of the forces that govern the DNA bending, molecular dynamics simulations were performed on a series of p53 core domain tetramer-DNA complexes in which each p53 core domain was bound to a DNA quarter site specifically. By varying the sequence of the central 4-base pairs of each half site, different DNA bending extents were observed. Our analysis shows that the interactions between p53 dimer-dimer were similar in all complexes; on the other hand, specific interactions between the p53 and DNA, including the interactions of Arg280, Lys120 and Arg248 with the DNA varied more significantly. In particular, the Arg280 interactions were better maintained in the complex with the CATG-containing DNA sequence, and were mostly lost in the complex with the CTAG-containing DNA sequence. Structural analysis shows that the base pairings for the CATG sequence were stable throughout the simulation trajectory while those for the CTAG sequence was partially dissociated in part of the trajectory, which affected the stability of nearby Arg280-Gua base interactions. Thus, DNA bending depends on the balance between the p53 dimer-dimer interactions and p53-DNA interactions, which in turn are related to the DNA sequence and DNA flexibility.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Analysis Of the P53-dna And The P53-p53 Interactionsmentioning

confidence: 99%

See 1 more Smart Citation

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Pan

Nussinov

2008

J. Phys. Chem. B

View full text Add to dashboard Cite

show abstract

“…Most p53 cancer mutations are located in the DNA-binding core domain of the protein (3). This domain has been structurally characterized in complex with its cognate DNA by x-ray crystallography (5,10,11) and in its free form in solution by NMR (12). It consists of a central ␤-sandwich that serves as a basic scaffold for the DNA-binding surface.…”

mentioning

confidence: 99%

Structural basis for understanding oncogenic p53 mutations and designing rescue drugs

Joerger

Ang

Fersht³

2006

Proc. Natl. Acad. Sci. U.S.A.

270

319

View full text Add to dashboard Cite

The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in Ϸ50% of human cancers. We have solved high-resolution crystal structures of several oncogenic mutants to investigate the structural basis of inactivation and provide information for designing drugs that may rescue inactivated mutants. We found a variety of structural consequences upon mutation: (i) the removal of an essential contact with DNA, (ii) creation of large, water-accessible crevices or hydrophobic internal cavities with no other structural changes but with a large loss of thermodynamic stability, (iii) distortion of the DNA-binding surface, and (iv) alterations to surfaces not directly involved in DNA binding but involved in domain-domain interactions on binding as a tetramer. These findings explain differences in functional properties and associated phenotypes (e.g., temperature sensitivity). Some mutants have the potential of being rescued by a generic stabilizing drug. In addition, a mutation-induced crevice is a potential target site for a mutant-selective stabilizing drug.cancer ͉ crystal ͉ structure ͉ drug design ͉ polymorphism T he tumor suppressor protein p53 is a 393-aa transcription factor that regulates the cell cycle and plays a key role in the prevention of cancer development. In response to oncogenic and other stresses, p53 induces the transcription of a number of target genes, resulting in cell-cycle arrest, senescence, or apoptosis (1, 2). In Ϸ50% of human cancers, p53 is inactivated as a result of missense mutation in the p53 gene (3, 4).The multifunctionality of p53 is reflected in the complexity of its structure. Each chain in the p53 tetramer is composed of several domains. There are well defined DNA-binding and tetramerization domains and highly mobile, largely unstructured regions (5-9). Most p53 cancer mutations are located in the DNA-binding core domain of the protein (3). This domain has been structurally characterized in complex with its cognate DNA by x-ray crystallography (5, 10, 11) and in its free form in solution by NMR (12). It consists of a central ␤-sandwich that serves as a basic scaffold for the DNA-binding surface. The DNA-binding surface is composed of two large loops (L2 and L3) that are stabilized by a zinc ion and a loop-sheet-helix motif. Together, these structural elements form an extended surface that makes specific contacts with the various p53 response elements. The six amino acid residues that are most frequently mutated in human cancer are located in or close to the DNA-binding surface (compare release R10 of the TP53 mutation database at www-p53.iarc.fr) (3). These residues have been classified as ''contact'' (Arg-248 and Arg-273) or ''structural'' (Arg-175, Gly-245, Arg-249, and Arg-282) residues, depending on whether they directly contact DNA or play a role in maintaining the structural integrity of the DNA-binding surface (Fig. 1) (5).Urea denaturation studies have shown that the contact mutation R273H has no effect on the thermodynamic stability of the core domain, wher...

show abstract

“…This however does not rule out the possibility that the DNA bound mutp53/p73 complex resembles the symmetrical p53 dimer because the latter is stabilized by interactions with DNA and by the formation of an extensive hydrogen-bonding network between the p53 monomers, connecting their Zn +2 clusters. 25 The DNA binding residues and the Zn +2 binding residues are conserved in p73 suggesting that similar stabilization of a pseudo-symmetrical DNA/p53/p73 complex can be achieved. The higher stability of the symmetrical DNA/wtp53 complex compared to DNA/wtp53/ p73 complex shifts the equilibrium in normal cells to formation of DNA bound wtp53 dimers.…”

Section: Resultsmentioning

confidence: 97%

The disruption of the protein complex mutantp53/p73 increases selectively the response of tumor cells to anticancer drugs

Agostino¹,

Cortese²,

Monti³

et al. 2008

Cell Cycle

View full text Add to dashboard Cite

Many in vitro and in vivo evidence have shown that the status of p53 is a key determinant in the response of tumor cells to anticancer treatment. Here we provide evidence that peptide-mediated targeting of the protein complex mutantp53/p73 enhances the response of mutant p53 tumor cells to commonly used anticancer drugs. Indeed, we show that the disruption of the protein complex mutantp53/p73 and the consequent restoration of p73 transcriptional effects, through the activity of short interfering peptides, render mutant p53 cells more prone to the killing of adriamycin and cisplatin. Of note, the activity of the short interfering peptides is mutant p53 specific and causes no effects on wt-p53 and p53 null cells. Our findings highlight the protein complex mutantp53/ p73 as a molecular target, whose successful overriding through the selective activity of small interfering peptides, might contribute to the optimization of mutant p53 tumor treatments.

show abstract

Structural Basis of DNA Recognition by p53 Tetramers

Cited by 366 publications

References 59 publications

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

p53-Induced DNA Bending: The Interplay between p53−DNA and p53−p53 Interactions

Structural basis for understanding oncogenic p53 mutations and designing rescue drugs

The disruption of the protein complex mutantp53/p73 increases selectively the response of tumor cells to anticancer drugs

Contact Info

Product

Resources

About