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PDBsum entry 3d05

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protein metals links
Transcription PDB id
3d05
Jmol
Contents
Protein chain
183 a.a. *
Metals
_ZN
Waters ×158
* Residue conservation analysis
PDB id:
3d05
Name: Transcription
Title: Human p53 core domain with hot spot mutation r249s (ii)
Structure: Cellular tumor antigen p53. Chain: a. Fragment: p53 core domain, unp residues 94-293. Synonym: tumor suppressor p53, phosphoprotein p53, antigen ny-co-13. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Gene: tp53. Expressed in: escherichia coli. Expression_system_taxid: 562.
Resolution:
1.70Å     R-factor:   0.221     R-free:   0.264
Authors: O.Suad,H.Rozenberg,L.J.W.Shimon,F.Frolow,Z.Shakked
Key ref:
O.Suad et al. (2009). Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations. J Mol Biol, 385, 249-265. PubMed id: 18996393 DOI: 10.1016/j.jmb.2008.10.063
Date:
01-May-08     Release date:   20-Jan-09    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P04637  (P53_HUMAN) -  Cellular tumor antigen p53
Seq:
Struc:
393 a.a.
183 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 1 residue position (black cross)

 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.jmb.2008.10.063 J Mol Biol 385:249-265 (2009)
PubMed id: 18996393  
 
 
Structural basis of restoring sequence-specific DNA binding and transactivation to mutant p53 by suppressor mutations.
O.Suad, H.Rozenberg, R.Brosh, Y.Diskin-Posner, N.Kessler, L.J.Shimon, F.Frolow, A.Liran, V.Rotter, Z.Shakked.
 
  ABSTRACT  
 
The tumor suppressor protein p53 is mutated in more than 50% of invasive cancers. About 30% of the mutations are found in six major "hot spot" codons located in its DNA binding core domain. To gain structural insight into the deleterious effects of such mutations and their rescue by suppressor mutations, we determined the crystal structures of the p53 core domain incorporating the hot spot mutation R249S, the core domain incorporating R249S and a second-site suppressor mutation H168R (referred to as the double mutant R249S/H168R) and its sequence-specific complex with DNA and of the triple mutant R249S/H168R/T123A. The structural studies were accompanied by transactivation and apoptosis experiments. The crystal structures show that the region at the vicinity of the mutation site in the R249S mutant displays a range of conformations [wild-type (wt) and several mutant-type conformations] due to the loss of stabilizing interactions mediated by R249 in the wt protein. As a consequence, the protein surface that is critical to the formation of functional p53-DNA complexes, through protein-protein and protein-DNA interactions, is largely distorted in the mutant conformations, thus explaining the protein's "loss of function" as a transcription factor. The structure of this region is restored in both R249S/H168R and R249S/H168R/T123A and is further stabilized in the complex of R249S/H168R with DNA. Our functional data show that the introduction of H168R as a second-site suppressor mutation partially restores the transactivation capacity of the protein and that this effect is further amplified by the addition of a third-site mutation T123A. These findings together with previously reported data on wt and mutant p53 provide a structural framework for understanding p53 dysfunction as a result of oncogenic mutations and its rescue by suppressor mutations and for a potential drug design aimed at restoring wt activity to aberrant p53 proteins.
 
  Selected figure(s)  
 
Figure 5.
Fig. 5. Dimerization surfaces. Stereo view of the superposition of core domain regions that form the symmetrical dimer interface upon DNA binding (one-half of the symmetrical dimer), including the nine structures of Fig. 1 (with the same color code) and the thermostable mutant T-p53C-R249S (PDB code 2BIO)^38 shown in light blue. The various structural elements (L2, L3, H1, H1″) and the boundaries of the corresponding regions (residues 168–195 and 236–250) are indicated. Zinc atoms are shown by the corresponding colored spheres.
Figure 8.
Fig. 8. Different views of the R249S/H168R tetramer bound to DNA. Four core domains (designated A–D) shown in ribbon representation interact with two double-stranded DNA half-sites (shown in grey). The core tetramer is a dimer of dimers: A, B (cyan and red) and C, D (green and magenta). (a) View down the central dyad of the core tetramer. (b) View perpendicular to the central dyad and the DNA helix axis. (c) View down the DNA helix axis.
 
  The above figures are reprinted by permission from Elsevier: J Mol Biol (2009, 385, 249-265) copyright 2009.  
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
  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.  
20696896 D.Coutandin, H.D.Ou, F.Löhr, and V.Dötsch (2010).
Tracing the protectors path from the germ line to the genome.
  Proc Natl Acad Sci U S A, 107, 15318-15325.  
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
  20700496 Y.Pan, and R.Nussinov (2010).
Lysine120 interactions with p53 response elements can allosterically direct p53 organization.
  PLoS Comput Biol, 6, 0.  
19717093 P.Hainaut, and K.G.Wiman (2009).
30 years and a long way into p53 research.
  Lancet Oncol, 10, 913-919.  
19693097 R.Brosh, and V.Rotter (2009).
When mutants gain new powers: news from the mutant p53 field.
  Nat Rev Cancer, 9, 701-713.  
19629163 Y.Pan, and R.Nussinov (2009).
Cooperativity dominates the genomic organization of p53-response elements: a mechanistic view.
  PLoS Comput Biol, 5, e1000448.  
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.