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PDBsum entry 2j20

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protein ligands metals Protein-protein interface(s) links
Nuclear protein PDB id
2j20
Jmol
Contents
Protein chains
195 a.a. *
Ligands
SO4 ×2
Metals
_ZN ×2
Waters ×382
* Residue conservation analysis
PDB id:
2j20
Name: Nuclear protein
Title: Human p53 core domain mutant m133l-v203a-n239y-n268d-r273c
Structure: Cellular tumor antigen p53. Chain: a, b. Fragment: DNA-binding core domain, residues 94-312. Synonym: p53, tumor suppressor p53, phosphoprotein p53, antigen ny-co-13. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
Resolution:
1.8Å     R-factor:   0.188     R-free:   0.206
Authors: A.C.Joerger,H.C.Ang,A.R.Fersht
Key ref:
A.C.Joerger et al. (2006). Structural basis for understanding oncogenic p53 mutations and designing rescue drugs. Proc Natl Acad Sci U S A, 103, 15056-15061. PubMed id: 17015838 DOI: 10.1073/pnas.0607286103
Date:
15-Aug-06     Release date:   20-Sep-06    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chains
Pfam   ArchSchema ?
P04637  (P53_HUMAN) -  Cellular tumor antigen p53
Seq:
Struc:
393 a.a.
195 a.a.*
Key:    PfamA domain  Secondary structure  CATH domain
* PDB and UniProt seqs differ at 5 residue positions (black crosses)

 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: 10.1073/pnas.0607286103 Proc Natl Acad Sci U S A 103:15056-15061 (2006)
PubMed id: 17015838  
 
 
Structural basis for understanding oncogenic p53 mutations and designing rescue drugs.
A.C.Joerger, H.C.Ang, A.R.Fersht.
 
  ABSTRACT  
 
The DNA-binding domain of the tumor suppressor p53 is inactivated by mutation in approximately 50% 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.
 
  Selected figure(s)  
 
Figure 4.
Fig. 4. Crystal structure of T-p53C-Y220C. (A) Stereoview of the mutation site at the periphery of the -sandwich in T-p53C-Y220C (PDB ID code 2J1X, molecule A, yellow) superimposed on the structure of T-p53C (PDB ID code 1UOL, molecule A, gray). Several water molecules close to Cys-220 in T-p53C-Y220C that fill the cleft created by the mutation are shown as red spheres. (B) Molecular surface of T-p53C around Tyr-220. (C) Molecular surface of T-p53C-Y220C. The view is the same as in B. The position of the side chain of Tyr-220 in T-p53C is shown as a stick model.
Figure 5.
Fig. 5. Crystal structures of T-p53C-V143A and T-p53C-F270L. (A) Stereoview of the structure of T-p53C-V143A (PDB ID code 2J1W, yellow) superimposed on T-p53C (PDB ID code 1UOL, gray). All residues in the hydrophobic core of the -sandwich within a 4.5-Å radius of the Val-143 side chain in T-p53C are shown. (B) Stereoview of the structure of T-p53C-F270L (PDB ID code 2J1Z, yellow) superimposed on T-p53C (PDB ID code 1UOL, gray). All residues within a 6-Å radius of the Phe-270 side chain in T-p53C are shown.
 
  Figures were selected by an automated process.  

Literature references that cite this PDB file's key reference

  PubMed id Reference
21097469 S.Rajagopalan, F.Huang, and A.R.Fersht (2011).
Single-Molecule characterization of oligomerization kinetics and equilibria of the tumor suppressor p53.
  Nucleic Acids Res, 39, 2294-2303.  
  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.  
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.  
19701813 J.H.Ko, H.S.Lee, J.Hong, and J.S.Hwang (2010).
Virilizing adrenocortical carcinoma in a child with Turner syndrome and somatic TP53 gene mutation.
  Eur J Pediatr, 169, 501-504.  
20407015 J.J.Jordan, A.Inga, K.Conway, S.Edmiston, L.A.Carey, L.Wu, and M.A.Resnick (2010).
Altered-function p53 missense mutations identified in breast cancers can have subtle effects on transactivation.
  Mol Cancer Res, 8, 701-716.  
20878668 J.L.Kaar, N.Basse, A.C.Joerger, E.Stephens, T.J.Rutherford, and A.R.Fersht (2010).
Stabilization of mutant p53 via alkylation of cysteines and effects on DNA binding.
  Protein Sci, 19, 2267-2278.  
20498645 K.G.Wiman (2010).
Pharmacological reactivation of mutant p53: from protein structure to the cancer patient.
  Oncogene, 29, 4245-4252.  
20436666 L.Goltermann, M.S.Larsen, R.Banerjee, A.C.Joerger, M.Ibba, and T.Bentin (2010).
Protein evolution via amino acid and codon elimination.
  PLoS One, 5, e10104.  
  20182602 M.Olivier, M.Hollstein, and P.Hainaut (2010).
TP53 mutations in human cancers: origins, consequences, and clinical use.
  Cold Spring Harb Perspect Biol, 2, a001008.  
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
20589832 R.E.Perez, C.D.Knights, G.Sahu, J.Catania, V.K.Kolukula, D.Stoler, A.Graessmann, V.Ogryzko, M.Pishvaian, C.Albanese, and M.L.Avantaggiati (2010).
Restoration of DNA-binding and growth-suppressive activity of mutant forms of p53 via a PCAF-mediated acetylation pathway.
  J Cell Physiol, 225, 394-405.  
20111584 X.Liu, and Y.P.Zhao (2010).
Switch region for pathogenic structural change in conformational disease and its prediction.
  PLoS One, 5, e8441.  
19935675 C.J.Brown, S.Lain, C.S.Verma, A.R.Fersht, and D.P.Lane (2009).
Awakening guardian angels: drugging the p53 pathway.
  Nat Rev Cancer, 9, 862-873.  
19667193 E.Natan, D.Hirschberg, N.Morgner, C.V.Robinson, and A.R.Fersht (2009).
Ultraslow oligomerization equilibria of p53 and its implications.
  Proc Natl Acad Sci U S A, 106, 14327-14332.  
22477774 F.Gorrec (2009).
The MORPHEUS protein crystallization screen.
  J Appl Crystallogr, 42, 1035-1042.  
19515728 K.H.Khoo, A.C.Joerger, S.M.Freund, and A.R.Fersht (2009).
Stabilising the DNA-binding domain of p53 by rational design of its hydrophobic core.
  Protein Eng Des Sel, 22, 421-430.
PDB code: 2wgx
19700401 K.H.Khoo, S.Mayer, and A.R.Fersht (2009).
Effects of stability on the biological function of p53.
  J Biol Chem, 284, 30974-30980.  
18802452 M.Olivier, A.Petitjean, V.Marcel, A.Pétré, M.Mounawar, A.Plymoth, C.C.de Fromentel, and P.Hainaut (2009).
Recent advances in p53 research: an interdisciplinary perspective.
  Cancer Gene Ther, 16, 1.  
19717093 P.Hainaut, and K.G.Wiman (2009).
30 years and a long way into p53 research.
  Lancet Oncol, 10, 913-919.  
19748724 Y.H.Tan, Y.M.Chen, X.Ye, Q.Lu, V.Tretyachenko-Ladokhina, W.Yang, D.F.Senear, and R.Luo (2009).
Molecular mechanisms of functional rescue mediated by P53 tumor suppressor mutations.
  Biophys Chem, 145, 37-44.  
18410249 A.C.Joerger, and A.R.Fersht (2008).
Structural biology of the tumor suppressor p53.
  Annu Rev Biochem, 77, 557-582.  
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
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
18621913 M.M.García-Alai, H.Tidow, E.Natan, F.M.Townsley, D.B.Veprintsev, and A.R.Fersht (2008).
The novel p53 isoform "delta p53" is a misfolded protein and does not bind the p21 promoter site.
  Protein Sci, 17, 1671-1678.  
18499664 R.P.Ghosh, R.A.Horowitz-Scherer, T.Nikitina, L.M.Gierasch, and C.L.Woodcock (2008).
Rett syndrome-causing mutations in human MeCP2 result in diverse structural changes that impact folding and DNA interactions.
  J Biol Chem, 283, 20523-20534.  
17609377 A.Argentaro, J.C.Yang, L.Chapman, M.S.Kowalczyk, R.J.Gibbons, D.R.Higgs, D.Neuhaus, and D.Rhodes (2007).
Structural consequences of disease-causing mutations in the ATRX-DNMT3-DNMT3L (ADD) domain of the chromatin-associated protein ATRX.
  Proc Natl Acad Sci U S A, 104, 11939-11944.
PDB codes: 2jm1 2ld1
17401432 A.C.Joerger, and A.R.Fersht (2007).
Structure-function-rescue: the diverse nature of common p53 cancer mutants.
  Oncogene, 26, 2226-2242.  
17401427 E.Kim, and W.Deppert (2007).
Interactions of mutant p53 with DNA: guilt by association.
  Oncogene, 26, 2185-2190.  
17428149 E.Sim, I.Westwood, and E.Fullam (2007).
Arylamine N-acetyltransferases.
  Expert Opin Drug Metab Toxicol, 3, 169-184.  
17401433 G.Selivanova, and K.G.Wiman (2007).
Reactivation of mutant p53: molecular mechanisms and therapeutic potential.
  Oncogene, 26, 2243-2254.  
17488404 I.Nindl, M.Gottschling, N.Krawtchenko, M.D.Lehmann, J.Röwert-Huber, J.Eberle, E.Stockfleth, and T.Forschner (2007).
Low prevalence of p53, p16(INK4a) and Ha-ras tumour-specific mutations in low-graded actinic keratosis.
  Br J Dermatol, 156, 34-39.  
17452350 I.W.Davis, A.Leaver-Fay, V.B.Chen, J.N.Block, G.J.Kapral, X.Wang, L.W.Murray, W.B.Arendall, J.Snoeyink, J.S.Richardson, and D.C.Richardson (2007).
MolProbity: all-atom contacts and structure validation for proteins and nucleic acids.
  Nucleic Acids Res, 35, W375-W383.  
17914225 J.D.Wright, and C.Lim (2007).
Mechanism of DNA-binding loss upon single-point mutation in p53.
  J Biosci, 32, 827-839.  
17401429 L.Weisz, M.Oren, and V.Rotter (2007).
Transcription regulation by mutant p53.
  Oncogene, 26, 2202-2211.  
17824689 Q.Lu, Y.H.Tan, and R.Luo (2007).
Molecular dynamics simulations of p53 DNA-binding domain.
  J Phys Chem B, 111, 11538-11545.  
17703463 V.De Grandis, A.R.Bizzarri, and S.Cannistraro (2007).
Docking study and free energy simulation of the complex between p53 DNA-binding domain and azurin.
  J Mol Recognit, 20, 215-226.  
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.