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PDBsum entry 2ahi

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protein dna_rna metals Protein-protein interface(s) links
Apoptosis/DNA PDB id
2ahi
Jmol
Contents
Protein chains
199 a.a. *
DNA/RNA
Metals
_ZN ×4
Waters ×998
* Residue conservation analysis
PDB id:
2ahi
Name: Apoptosis/DNA
Title: Structural basis of DNA recognition by p53 tetramers (complex iii)
Structure: 5'-d( Cp Gp Gp Ap Cp Ap Tp Gp Tp Cp Cp G)-3'. Chain: e, f, g, h. Synonym: tumor suppressor p53, phosphoprotein p53, antigen ny-co-13. Engineered: yes. Cellular tumor antigen p53. Chain: a, b, c, d. Fragment: residues 94-293. Engineered: yes
Source: Synthetic: yes. Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562.
Biol. unit: Tetramer (from PQS)
Resolution:
1.85Å     R-factor:   0.166     R-free:   0.225
Authors: M.Kitayner,H.Rozenberg,N.Kessler,D.Rabinovich,Z.Shakked
Key ref:
M.Kitayner et al. (2006). Structural basis of DNA recognition by p53 tetramers. Mol Cell, 22, 741-753. PubMed id: 16793544 DOI: 10.1016/j.molcel.2006.05.015
Date:
28-Jul-05     Release date:   11-Jul-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P04637  (P53_HUMAN) -  Cellular tumor antigen p53
Seq:
Struc:
393 a.a.
199 a.a.
Key:    PfamA domain  Secondary structure  CATH domain

 Gene Ontology (GO) functional annotation 
  GO annot!
  Cellular component     nucleus   1 term 
  Biological process     apoptotic process   2 terms 
  Biochemical function     transcription regulatory region DNA binding     3 terms  

 

 
DOI no: 10.1016/j.molcel.2006.05.015 Mol Cell 22:741-753 (2006)
PubMed id: 16793544  
 
 
Structural basis of DNA recognition by p53 tetramers.
M.Kitayner, H.Rozenberg, N.Kessler, D.Rabinovich, L.Shaulov, T.E.Haran, Z.Shakked.
 
  ABSTRACT  
 
The tumor-suppressor protein p53 is among the most effective of the cell's natural defenses against cancer. In response to cellular stress, p53 binds as a tetramer to diverse DNA targets containing two decameric half-sites, thereby activating the expression of genes involved in cell-cycle arrest or apoptosis. Here we present high-resolution crystal structures of sequence-specific complexes between the core domain of human p53 and different DNA half-sites. In all structures, four p53 molecules self-assemble on two DNA half-sites to form a tetramer that is a dimer of dimers, stabilized by protein-protein and base-stacking interactions. The protein-DNA interface varies as a function of the specific base sequence in correlation with the measured binding affinities of the complexes. The new data establish a structural framework for understanding the mechanisms of specificity, affinity, and cooperativity of DNA binding by p53 and suggest a model for its regulation by regions outside the sequence-specific DNA binding domain.
 
  Selected figure(s)  
 
Figure 2.
Figure 2. Stereo Views of the Symmetrical Protein-Protein Interface
Figure 7.
Figure 7. A Model for Full-Length p53 Tetramer Bound to DNA
 
  The above figures are reprinted by permission from Cell Press: Mol Cell (2006, 22, 741-753) copyright 2006.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21178072 A.Tafvizi, F.Huang, A.R.Fersht, L.A.Mirny, and A.M.van Oijen (2011).
A single-molecule characterization of p53 search on DNA.
  Proc Natl Acad Sci U S A, 108, 563-568.  
21464285 C.Chen, N.Gorlatova, Z.Kelman, and O.Herzberg (2011).
Structures of p63 DNA binding domain in complexes with half-site and with spacer-containing full response elements.
  Proc Natl Acad Sci U S A, 108, 6456-6461.
PDB codes: 3qym 3qyn
21208455 F.Cui, M.V.Sirotin, and V.B.Zhurkin (2011).
Impact of Alu repeats on the evolution of human p53 binding sites.
  Biol Direct, 6, 2.  
21458306 H.S.Bandukwala, Y.Wu, M.Feuerer, Y.Chen, B.Barboza, S.Ghosh, J.C.Stroud, C.Benoist, D.Mathis, A.Rao, and L.Chen (2011).
Structure of a domain-swapped FOXP3 dimer on DNA and its function in regulatory T cells.
  Immunity, 34, 479-491.
PDB code: 3qrf
21071400 I.Beno, K.Rosenthal, M.Levitine, L.Shaulov, and T.E.Haran (2011).
Sequence-dependent cooperative binding of p53 to DNA targets and its relationship to the structural properties of the DNA targets.
  Nucleic Acids Res, 39, 1919-1932.  
20966976 I.Goldstein, V.Marcel, M.Olivier, M.Oren, V.Rotter, and P.Hainaut (2011).
Understanding wild-type and mutant p53 activities in human cancer: new landmarks on the way to targeted therapies.
  Cancer Gene Ther, 18, 2.  
21338609 N.Khazanov, and Y.Levy (2011).
Sliding of p53 along DNA can be modulated by its oligomeric state and by cross-talks between its constituent domains.
  J Mol Biol, 408, 335-355.  
21178074 R.Melero, S.Rajagopalan, M.Lázaro, A.C.Joerger, T.Brandt, D.B.Veprintsev, G.Lasso, D.Gil, S.H.Scheres, J.M.Carazo, A.R.Fersht, and M.Valle (2011).
Electron microscopy studies on the quaternary structure of p53 reveal different binding modes for p53 tetramers in complex with DNA.
  Proc Natl Acad Sci U S A, 108, 557-562.  
21253649 S.M.Quintal, Q.A.dePaula, and N.P.Farrell (2011).
Zinc finger proteins as templates for metal ion exchange and ligand reactivity. Chemical and biological consequences.
  Metallomics, 3, 121-139.  
21522129 T.J.Petty, S.Emamzadah, L.Costantino, I.Petkova, E.S.Stavridi, J.G.Saven, E.Vauthey, and T.D.Halazonetis (2011).
An induced fit mechanism regulates p53 DNA binding kinetics to confer sequence specificity.
  EMBO J, 30, 2167-2176.
PDB codes: 3q01 3q05 3q06
  20516128 A.C.Joerger, and A.R.Fersht (2010).
The tumor suppressor p53: from structures to drug discovery.
  Cold Spring Harb Perspect Biol, 2, a000919.  
20113312 A.Merabet, H.Houlleberghs, K.Maclagan, E.Akanho, T.T.Bui, B.Pagano, A.F.Drake, F.Fraternali, and P.V.Nikolova (2010).
Mutants of the tumour suppressor p53 L1 loop as second-site suppressors for restoring DNA binding to oncogenic p53 mutations: structural and biochemical insights.
  Biochem J, 427, 225-236.  
20644729 A.Yang, Z.Zhu, A.Kettenbach, P.Kapranov, F.McKeon, T.R.Gingeras, and K.Struhl (2010).
Genome-wide mapping indicates that p73 and p63 co-occupy target sites and have similar dna-binding profiles in vivo.
  PLoS One, 5, e11572.  
20080630 D.Menendez, A.Inga, and M.A.Resnick (2010).
Estrogen receptor acting in cis enhances WT and mutant p53 transactivation at canonical and noncanonical p53 target sequences.
  Proc Natl Acad Sci U S A, 107, 1500-1505.  
19887449 G.Sahu, D.Wang, C.B.Chen, V.B.Zhurkin, R.E.Harrington, E.Appella, G.L.Hager, and A.K.Nagaich (2010).
p53 binding to nucleosomal DNA depends on the rotational positioning of DNA response element.
  J Biol Chem, 285, 1321-1332.  
20446770 J.Shlomai (2010).
Redox control of protein-DNA interactions: from molecular mechanisms to significance in signal transduction, gene expression, and DNA replication.
  Antioxid Redox Signal, 13, 1429-1476.  
20364130 M.Kitayner, H.Rozenberg, R.Rohs, O.Suad, D.Rabinovich, B.Honig, and Z.Shakked (2010).
Diversity in DNA recognition by p53 revealed by crystal structures with Hoogsteen base pairs.
  Nat Struct Mol Biol, 17, 423-429.
PDB codes: 3igk 3igl 3kz8
20142040 N.Basse, J.L.Kaar, G.Settanni, A.C.Joerger, T.J.Rutherford, and A.R.Fersht (2010).
Toward the rational design of p53-stabilizing drugs: probing the surface of the oncogenic Y220C mutant.
  Chem Biol, 17, 46-56.
PDB codes: 2x0u 2x0v 2x0w
20190809 P.Li, D.Wang, H.Yao, P.Doret, G.Hao, Q.Shen, H.Qiu, X.Zhang, Y.Wang, G.Chen, and Y.Wang (2010).
Coordination of PAD4 and HDAC2 in the regulation of p53-target gene expression.
  Oncogene, 29, 3153-3162.  
20334529 R.Rohs, X.Jin, S.M.West, R.Joshi, B.Honig, and R.S.Mann (2010).
Origins of specificity in protein-DNA recognition.
  Annu Rev Biochem, 79, 233-269.  
20368720 S.Chitayat, and C.H.Arrowsmith (2010).
Four p(53)s in a pod.
  Nat Struct Mol Biol, 17, 390-391.  
20483917 S.R.Bowers, F.J.Calero-Nieto, S.Valeaux, N.Fernandez-Fuentes, and P.N.Cockerill (2010).
Runx1 binds as a dimeric complex to overlapping Runx1 sites within a palindromic element in the human GM-CSF enhancer.
  Nucleic Acids Res, 38, 6124-6134.  
  20516129 V.A.Belyi, P.Ak, E.Markert, H.Wang, W.Hu, A.Puzio-Kuter, and A.J.Levine (2010).
The origins and evolution of the p53 family of genes.
  Cold Spring Harb Perspect Biol, 2, a001198.  
20159469 Y.Chen, R.Dey, and L.Chen (2010).
Crystal structure of the p53 core domain bound to a full consensus site as a self-assembled tetramer.
  Structure, 18, 246-256.
PDB code: 3kmd
  20700496 Y.Pan, and R.Nussinov (2010).
Lysine120 interactions with p53 response elements can allosterically direct p53 organization.
  PLoS Comput Biol, 6, 0.  
19815500 A.C.Joerger, S.Rajagopalan, E.Natan, D.B.Veprintsev, C.V.Robinson, and A.R.Fersht (2009).
Structural evolution of p53, p63, and p73: implication for heterotetramer formation.
  Proc Natl Acad Sci U S A, 106, 17705-17710.
PDB codes: 2wqi 2wqj 2wtt
19286366 A.L.Okorokov, and E.V.Orlova (2009).
Structural biology of the p53 tumour suppressor.
  Curr Opin Struct Biol, 19, 197-202.  
19776742 D.Menendez, A.Inga, and M.A.Resnick (2009).
The expanding universe of p53 targets.
  Nat Rev Cancer, 9, 724-737.  
18978813 K.A.Malecka, W.C.Ho, and R.Marmorstein (2009).
Crystal structure of a p53 core tetramer bound to DNA.
  Oncogene, 28, 325-333.
PDB codes: 3exj 3exl
19556538 K.Allton, A.K.Jain, H.M.Herz, W.W.Tsai, S.Y.Jung, J.Qin, A.Bergmann, R.L.Johnson, and M.C.Barton (2009).
Trim24 targets endogenous p53 for degradation.
  Proc Natl Acad Sci U S A, 106, 11612-11616.  
19410540 K.H.Vousden, and C.Prives (2009).
Blinded by the Light: The Growing Complexity of p53.
  Cell, 137, 413-431.  
19362815 R.Rohs, S.M.West, P.Liu, and B.Honig (2009).
Nuance in the double-helix and its role in protein-DNA recognition.
  Curr Opin Struct Biol, 19, 171-177.  
19494119 S.M.Sykes, T.J.Stanek, A.Frank, M.E.Murphy, and S.B.McMahon (2009).
Acetylation of the DNA binding domain regulates transcription-independent apoptosis by p53.
  J Biol Chem, 284, 20197-20205.  
19525231 S.Rajagopalan, A.Andreeva, D.P.Teufel, S.M.Freund, and A.R.Fersht (2009).
Interaction between the Transactivation Domain of p53 and PC4 Exemplifies Acidic Activation Domains as Single-stranded DNA Mimics.
  J Biol Chem, 284, 21728-21737.  
19624732 S.Sollner, and P.Macheroux (2009).
New roles of flavoproteins in molecular cell biology: an unexpected role for quinone reductases as regulators of proteasomal degradation.
  FEBS J, 276, 4313-4324.  
19339993 S.Y.Wu, and C.M.Chiang (2009).
Crosstalk between sumoylation and acetylation regulates p53-dependent chromatin transcription and DNA binding.
  EMBO J, 28, 1246-1259.  
20030809 T.Brandt, M.Petrovich, A.C.Joerger, and D.B.Veprintsev (2009).
Conservation of DNA-binding specificity and oligomerisation properties within the p53 family.
  BMC Genomics, 10, 628.  
19629163 Y.Pan, and R.Nussinov (2009).
Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
  PLoS Comput Biol, 5, e1000448.  
  19558684 Y.Tan, and R.Luo (2009).
Structural and functional implications of p53 missense cancer mutations.
  PMC Biophys, 2, 5.  
19477430 Y.Wang, J.Yang, H.Zheng, G.J.Tomasek, P.Zhang, P.E.McKeever, E.Y.Lee, and Y.Zhu (2009).
Expression of mutant p53 proteins implicates a lineage relationship between neural stem cells and malignant astrocytic glioma in a murine model.
  Cancer Cell, 15, 514-526.  
18410249 A.C.Joerger, and A.R.Fersht (2008).
Structural biology of the tumor suppressor p53.
  Annu Rev Biochem, 77, 557-582.  
18648687 A.I.Anzellotti, and N.P.Farrell (2008).
Zinc metalloproteins as medicinal targets.
  Chem Soc Rev, 37, 1629-1651.  
18511808 A.J.Okumura, L.F.Peterson, F.Okumura, A.Boyapati, and D.E.Zhang (2008).
t(8;21)(q22;q22) Fusion proteins preferentially bind to duplicated AML1/RUNX1 DNA-binding sequences to differentially regulate gene expression.
  Blood, 112, 1392-1401.  
18315848 A.Madhumalar, D.J.Smith, and C.Verma (2008).
Stability of the core domain of p53: insights from computer simulations.
  BMC Bioinformatics, 9, S17.  
18453682 C.Tu, Y.H.Tan, G.Shaw, Z.Zhou, Y.Bai, R.Luo, and X.Ji (2008).
Impact of low-frequency hotspot mutation R282Q on the structure of p53 DNA-binding domain as revealed by crystallography at 1.54 angstroms resolution.
  Acta Crystallogr D Biol Crystallogr, 64, 471-477.
PDB code: 2pcx
18234719 D.B.Veprintsev, and A.R.Fersht (2008).
Algorithm for prediction of tumour suppressor p53 affinity for binding sites in DNA.
  Nucleic Acids Res, 36, 1589-1598.  
17972286 D.F.Lowry, A.Stancik, R.M.Shrestha, and G.W.Daughdrill (2008).
Modeling the accessible conformations of the intrinsically unstructured transactivation domain of p53.
  Proteins, 71, 587-598.  
18673581 E.Hodis, J.Prilusky, E.Martz, I.Silman, J.Moult, and J.L.Sussman (2008).
Proteopedia - a scientific 'wiki' bridging the rift between three-dimensional structure and function of biomacromolecules.
  Genome Biol, 9, R121.  
18650397 F.M.Boeckler, A.C.Joerger, G.Jaggi, T.J.Rutherford, D.B.Veprintsev, and A.R.Fersht (2008).
Targeted rescue of a destabilized mutant of p53 by an in silico screened drug.
  Proc Natl Acad Sci U S A, 105, 10360-10365.
PDB code: 2vuk
18714371 J.J.Jordan, D.Menendez, A.Inga, M.Nourredine, D.Bell, and M.A.Resnick (2008).
Noncanonical DNA motifs as transactivation targets by wild type and mutant p53.
  PLoS Genet, 4, e1000104.  
18547443 K.Heyne, K.Schmitt, D.Mueller, V.Armbruester, P.Mestres, and K.Roemer (2008).
Resistance of mitochondrial p53 to dominant inhibition.
  Mol Cancer, 7, 54.  
18474530 L.Smeenk, S.J.van Heeringen, M.Koeppel, M.A.van Driel, S.J.Bartels, R.C.Akkers, S.Denissov, H.G.Stunnenberg, and M.Lohrum (2008).
Characterization of genome-wide p53-binding sites upon stress response.
  Nucleic Acids Res, 36, 3639-3654.  
18676809 M.L.Kilkenny, A.S.Doré, S.M.Roe, K.Nestoras, J.C.Ho, F.Z.Watts, and L.H.Pearl (2008).
Structural and functional analysis of the Crb2-BRCT2 domain reveals distinct roles in checkpoint signaling and DNA damage repair.
  Genes Dev, 22, 2034-2047.
PDB codes: 2vxb 2vxc
18391200 M.Wells, H.Tidow, T.J.Rutherford, P.Markwick, M.R.Jensen, E.Mylonas, D.I.Svergun, M.Blackledge, and A.R.Fersht (2008).
Structure of tumor suppressor p53 and its intrinsically disordered N-terminal transactivation domain.
  Proc Natl Acad Sci U S A, 105, 5762-5767.  
18505818 P.Li, H.Yao, Z.Zhang, M.Li, Y.Luo, P.R.Thompson, D.S.Gilmour, and Y.Wang (2008).
Regulation of p53 target gene expression by peptidylarginine deiminase 4.
  Mol Cell Biol, 28, 4745-4758.  
18461991 Y.Pan, and R.Nussinov (2008).
p53-Induced DNA bending: the interplay between p53-DNA and p53-p53 interactions.
  J Phys Chem B, 112, 6716-6724.  
17401432 A.C.Joerger, and A.R.Fersht (2007).
Structure-function-rescue: the diverse nature of common p53 cancer mutants.
  Oncogene, 26, 2226-2242.  
17986463 B.Ma, and A.J.Levine (2007).
Probing potential binding modes of the p53 tetramer to DNA based on the symmetries encoded in p53 response elements.
  Nucleic Acids Res, 35, 7733-7747.  
17439973 B.Ma, Y.Pan, J.Zheng, A.J.Levine, and R.Nussinov (2007).
Sequence analysis of p53 response-elements suggests multiple binding modes of the p53 tetramer to DNA targets.
  Nucleic Acids Res, 35, 2986-3001.  
17699158 B.Sot, S.M.Freund, and A.R.Fersht (2007).
Comparative biophysical characterization of p53 with the pro-apoptotic BAK and the anti-apoptotic BCL-xL.
  J Biol Chem, 282, 29193-29200.  
17290219 C.J.Matheny, M.E.Speck, P.R.Cushing, Y.Zhou, T.Corpora, M.Regan, M.Newman, L.Roudaia, C.L.Speck, T.L.Gu, S.M.Griffey, J.H.Bushweller, and N.A.Speck (2007).
Disease mutations in RUNX1 and RUNX2 create nonfunctional, dominant-negative, or hypomorphic alleles.
  EMBO J, 26, 1163-1175.  
17401428 D.Menendez, A.Inga, J.J.Jordan, and M.A.Resnick (2007).
Changing the p53 master regulatory network: ELEMENTary, my dear Mr Watson.
  Oncogene, 26, 2191-2201.  
17893322 F.A.Atcha, A.Syed, B.Wu, N.P.Hoverter, N.N.Yokoyama, J.H.Ting, J.E.Munguia, H.J.Mangalam, J.L.Marsh, and M.L.Waterman (2007).
A unique DNA binding domain converts T-cell factors into strong Wnt effectors.
  Mol Cell Biol, 27, 8352-8363.  
17620598 H.Tidow, R.Melero, E.Mylonas, S.M.Freund, J.G.Grossmann, J.M.Carazo, D.I.Svergun, M.Valle, and A.R.Fersht (2007).
Quaternary structures of tumor suppressor p53 and a specific p53 DNA complex.
  Proc Natl Acad Sci U S A, 104, 12324-12329.  
17526530 H.Tjong, S.Qin, and H.X.Zhou (2007).
PI2PE: protein interface/interior prediction engine.
  Nucleic Acids Res, 35, W357-W362.  
17170001 M.Lokshin, Y.Li, C.Gaiddon, and C.Prives (2007).
p53 and p73 display common and distinct requirements for sequence specific binding to DNA.
  Nucleic Acids Res, 35, 340-352.  
17429838 P.Das, D.Kotilingam, B.Korchin, J.Liu, D.Yu, A.J.Lazar, R.E.Pollock, and D.Lev (2007).
High prevalence of p53 exon 4 mutations in soft tissue sarcoma.
  Cancer, 109, 2323-2333.  
17085447 Y.Pan, and R.Nussinov (2007).
Structural basis for p53 binding-induced DNA bending.
  J Biol Chem, 282, 691-699.  
17327663 Y.Wang, A.Rosengarth, and H.Luecke (2007).
Structure of the human p53 core domain in the absence of DNA.
  Acta Crystallogr D Biol Crystallogr, 63, 276-281.
PDB code: 2ocj
17640907 Z.Shakked (2007).
Quaternary structure of p53: the light at the end of the tunnel.
  Proc Natl Acad Sci U S A, 104, 12231-12232.  
17015838 A.C.Joerger, H.C.Ang, and A.R.Fersht (2006).
Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.
  Proc Natl Acad Sci U S A, 103, 15056-15061.
PDB codes: 2j1w 2j1x 2j1y 2j1z 2j20 2j21
17053786 A.L.Okorokov, M.B.Sherman, C.Plisson, V.Grinkevich, K.Sigmundsson, G.Selivanova, J.Milner, and E.V.Orlova (2006).
The structure of p53 tumour suppressor protein reveals the basis for its functional plasticity.
  EMBO J, 25, 5191-5200.  
16887812 H.Tidow, D.B.Veprintsev, S.M.Freund, and A.R.Fersht (2006).
Effects of oncogenic mutations and DNA response elements on the binding of p53 to p53-binding protein 2 (53BP2).
  J Biol Chem, 281, 32526-32533.  
17189187 S.M.Sykes, H.S.Mellert, M.A.Holbert, K.Li, R.Marmorstein, W.S.Lane, and S.B.McMahon (2006).
Acetylation of the p53 DNA-binding domain regulates apoptosis induction.
  Mol Cell, 24, 841-851.  
17189182 S.Tyteca, G.Legube, and D.Trouche (2006).
To die or not to die: a HAT trick.
  Mol Cell, 24, 807-808.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time. Where a reference describes a PDB structure, the PDB codes are shown on the right.