PDBsum entry 2x0u

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protein ligands metals Protein-protein interface(s) links
Cell cycle PDB id
Protein chains
195 a.a. *
_ZN ×2
Waters ×656
* Residue conservation analysis
PDB id:
Name: Cell cycle
Title: Structure of the p53 core domain mutant y220c bound to a 2- amino substituted benzothiazole scaffold
Structure: Cellular tumor antigen p53. Chain: a, b. Fragment: DNA-binding domain, residues 94-312. Synonym: tumor suppressor p53, phosphoprotein p53, antigen ny-co-13, p53. Engineered: yes. Mutation: yes
Source: Homo sapiens. Human. Organism_taxid: 9606. Expressed in: escherichia coli. Expression_system_taxid: 562
1.60Å     R-factor:   0.166     R-free:   0.193
Authors: A.C.Joerger,J.L.Kaar,N.Basse,A.R.Fersht
Key ref: N.Basse et al. (2010). Toward the rational design of p53-stabilizing drugs: probing the surface of the oncogenic Y220C mutant. Chem Biol, 17, 46-56. PubMed id: 20142040
17-Dec-09     Release date:   26-Jan-10    
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Protein chains
Pfam   ArchSchema ?
P04637  (P53_HUMAN) -  Cellular tumor antigen p53
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  


Chem Biol 17:46-56 (2010)
PubMed id: 20142040  
Toward the rational design of p53-stabilizing drugs: probing the surface of the oncogenic Y220C mutant.
N.Basse, J.L.Kaar, G.Settanni, A.C.Joerger, T.J.Rutherford, A.R.Fersht.
The p53 cancer mutation Y220C induces formation of a cavity on the protein's surface that can accommodate stabilizing small molecules. We combined fragment screening and molecular dynamics to assess the druggability of p53-Y220C and map ligand interaction sites within the mutational cavity. Elucidation of the binding mode of fragment hits by crystallography yielded a clear picture of how a drug might dock in the cavity. Simulations that solvate the protein with isopropanol found additional sites that extend the druggable surface. Moreover, structural observations and simulation revealed the dynamic landscape of the cavity, which improves our understanding of the impact of the mutation on p53 stability. This underpins the importance of considering flexibility of the cavity in screening for optimized ligands. Our findings provide a blueprint for the design of effective drugs that rescue p53-Y220C.

Literature references that cite this PDB file's key reference

  PubMed id Reference
20685816 A.Alibés, A.D.Nadra, F.De Masi, M.L.Bulyk, L.Serrano, and F.Stricher (2010).
Using protein design algorithms to understand the molecular basis of disease caused by protein-DNA interactions: the Pax6 example.
  Nucleic Acids Res, 38, 7422-7431.  
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.  
20656489 M.M.Maslon, and T.R.Hupp (2010).
Drug discovery and mutant p53.
  Trends Cell Biol, 20, 542-555.  
20520657 R.Huang, I.Martinez-Ferrando, and P.A.Cole (2010).
Enhanced interrogation: emerging strategies for cell signaling inhibition.
  Nat Struct Mol Biol, 17, 646-649.  
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