1UOL

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

Summary for 1UOL

• Entry DOI: 10.2210/pdb1uol/pdb
• Related: 1A1U 1AIE 1DT7 1GZH 1H26 1HS5 1KZY 1MA3 1OLG 1OLH 1PES 1PET 1SAE 1SAF 1SAG 1SAH 1SAI 1SAJ 1SAK 1SAL 1TSR 1TUP 1YCQ 1YCR 1YCS 3SAK
• Descriptor: CELLULAR TUMOR ANTIGEN P53, ZINC ION (3 entities in total)
• Functional Keywords: dna-binding protein, p53, dna-binding domain, tumor suppressor, second-site suppressor mutation, superstable mutant, apoptosis, transcription regulation, dna binding protein
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Cytoplasm. Isoform 1: Nucleus. Isoform 2: Nucleus. Isoform 3: Nucleus. Isoform 4: Nucleus. Isoform 7: Nucleus. Isoform 8: Nucleus. Isoform 9: Cytoplasm: P04637
• Total number of polymer chains: 2
• Total formula weight: 49312.50

Authors

Joerger, A.C.,Allen, M.D.,Fersht, A.R. (deposition date: 2003-09-19, release date: 2003-10-16, Last modification date: 2024-05-08)

Primary citation

Joerger, A.C.,Allen, M.D.,Fersht, A.R.
Crystal Structure of a Superstable Mutant of Human P53 Core Domain. Insights Into the Mechanism of Rescuing Oncogenic Mutations
J.Biol.Chem., 279:1291-, 2004

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.

PubMed: 14534297
DOI: 10.1074/JBC.M309732200

Experimental method

X-RAY DIFFRACTION (1.9 Å)