2J1W

Human p53 core domain mutant M133L-V143A-V203A-N239Y-N268D

Summary for 2J1W

• Entry DOI: 10.2210/pdb2j1w/pdb
• Related: 1HU8 1UOL 2BIM 2BIN 2BIO 2BIP 2BIQ 2J1X 2J1Y 2J1Z 2J20 2J21
• Descriptor: CELLULAR TUMOR ANTIGEN P53, ZINC ION (3 entities in total)
• Functional Keywords: second-site suppressor mutation, disease mutation, nuclear protein, phosphorylation, tumor suppressor, alternative splicing, li-fraumeni syndrome, li- fraumeni syndrome, host-virus interaction, transcription, metal-binding, anti-oncogene, dna-binding, transferase, polymorphism, glycoprotein, zinc, activator, apoptosis, cell cycle, acetylation, p53 dna-binding domain, transcription regulation, superstable mutant, 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: 49256.40

Authors

Joerger, A.C.,Fersht, A.R. (deposition date: 2006-08-15, release date: 2006-09-20, Last modification date: 2023-12-13)

Primary citation

Joerger, A.C.,Ang, H.C.,Fersht, A.R.
Structural Basis for Understanding Oncogenic P53 Mutations and Designing Rescue Drugs.
Proc.Natl.Acad.Sci.USA, 103:15056-, 2006

PubMed 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.

PubMed: 17015838
DOI: 10.1073/PNAS.0607286103

Experimental method

X-RAY DIFFRACTION (1.8 Å)