1UOL

Crystal structure of the human p53 core domain mutant M133L/V203A/N239Y/N268D at 1.9 A resolution.


Experimental Data Snapshot

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.192 

wwPDB Validation   3D Report Full Report


This is version 1.3 of the entry. See complete history


Literature

Crystal Structure of a Superstable Mutant of Human P53 Core Domain. Insights Into the Mechanism of Rescuing Oncogenic Mutations

Joerger, A.C.Allen, M.D.Fersht, A.R.

(2004) J Biol Chem 279: 1291

  • DOI: https://doi.org/10.1074/jbc.M309732200
  • Primary Citation of Related Structures:  
    1UOL

  • PubMed Abstract: 

    Most of the cancer-associated mutations in the tumor suppressor p53 map to its DNA-binding core domain. Many of them inactivate p53 by decreasing its thermodynamic stability. We have previously designed the superstable quadruple mutant M133L/V203A/N239Y/N268D containing the second-site suppressor mutations N239Y and N268D, which specifically restore activity and stability in several oncogenic mutants. Here we present the x-ray structure of this quadruple mutant at 1.9 A resolution, which was solved in a new crystal form in the absence of DNA. This structure reveals that the four point mutations cause only small local structural changes, whereas the overall structure of the central beta-sandwich and the DNA-binding surface is conserved. The suppressor mutation N268D results in an altered hydrogen bond pattern connecting strands S1 and S10, thus bridging the two sheets of the beta-sandwich scaffold in an energetically more favorable way. The second suppressor mutation N239Y, which is located in close proximity to the DNA-binding surface in loop L3, seems to reduce the plasticity of the structure in large parts of loop L3 as indicated by decreased crystallographic temperature factors. The same is observed for residues in the vicinity of the N268D substitution. This increase in rigidity provides the structural basis for the increase in thermostability and an understanding how N268D and N239Y rescue some of the common cancer mutants.


  • Organizational Affiliation

    Cambridge Centre for Protein Engineering, MRC Centre, Hills Road, Cambridge CB2 2QH, UK.


Macromolecules
Find similar proteins by:  (by identity cutoff)  |  3D Structure
Entity ID: 1
MoleculeChains Sequence LengthOrganismDetailsImage
CELLULAR TUMOR ANTIGEN P53
A, B
219Homo sapiensMutation(s): 4 
UniProt & NIH Common Fund Data Resources
Find proteins for P04637 (Homo sapiens)
Explore P04637 
Go to UniProtKB:  P04637
PHAROS:  P04637
GTEx:  ENSG00000141510 
Entity Groups  
Sequence Clusters30% Identity50% Identity70% Identity90% Identity95% Identity100% Identity
UniProt GroupP04637
Sequence Annotations
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  • Reference Sequence
Experimental Data & Validation

Experimental Data

  • Method: X-RAY DIFFRACTION
  • Resolution: 1.90 Å
  • R-Value Free: 0.230 
  • R-Value Work: 0.192 
  • R-Value Observed: 0.192 
  • Space Group: P 21 21 21
Unit Cell:
Length ( Å )Angle ( ˚ )
a = 65α = 90
b = 71β = 90
c = 104.8γ = 90
Software Package:
Software NamePurpose
CNSrefinement
CNSphasing

Structure Validation

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Entry History 

Deposition Data

Revision History  (Full details and data files)

  • Version 1.0: 2003-10-16
    Type: Initial release
  • Version 1.1: 2011-05-08
    Changes: Version format compliance
  • Version 1.2: 2011-07-13
    Changes: Version format compliance
  • Version 1.3: 2024-05-08
    Changes: Data collection, Database references, Derived calculations, Other