2j1x
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HUMAN P53 CORE DOMAIN MUTANT M133L-V203A-Y220C-N239Y-N268D
OverviewOverview
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.
DiseaseDisease
Known diseases associated with this structure: Adrenal cortical carcinoma OMIM:[191170], Breast cancer OMIM:[191170], Colorectal cancer OMIM:[191170], Hepatocellular carcinoma OMIM:[191170], Histiocytoma OMIM:[191170], Li-Fraumeni syndrome OMIM:[191170], Multiple malignancy syndrome OMIM:[191170], Nasopharyngeal carcinoma OMIM:[191170], Osteosarcoma OMIM:[191170], Pancreatic cancer OMIM:[191170], Thyroid carcinoma OMIM:[191170]
About this StructureAbout this Structure
2J1X is a Single protein structure of sequence from Homo sapiens with as ligand. Known structural/functional Site: . Full crystallographic information is available from OCA.
ReferenceReference
Structural basis for understanding oncogenic p53 mutations and designing rescue drugs., Joerger AC, Ang HC, Fersht AR, Proc Natl Acad Sci U S A. 2006 Oct 10;103(41):15056-61. Epub 2006 Oct 2. PMID:17015838
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- Homo sapiens
- Single protein
- Fersht, A R.
- Joerger, A C.
- ZN
- Acetylation
- Activator
- Alternative splicing
- Anti-oncogene
- Apoptosis
- Cell cycle
- Disease mutation
- Dna-binding
- Dna-binding protein
- Glycoprotein
- Host-virus interaction
- Li-fraumeni syndrome
- Metal-binding
- Nuclear protein
- P53 dna-binding domain
- Phosphorylation
- Polymorphism
- Second-site suppressor mutation
- Superstable mutant
- Transcription
- Transcription regulation
- Transferase
- Tumor suppressor
- Zinc