2j1x

File:2j1x.gif

spinqualitylabelsall models 2j1x, resolution 1.65Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image

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.

About this StructureAbout this Structure

2J1X is a Single protein structure of sequence from Homo sapiens with ZN as ligand. Structure known Active Site: AC1. 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

Page seeded by OCA on Mon Nov 5 18:23:18 2007