2J1X: Human P53 Core Domain Mutant M133l-V203a-Y220c-N239y-N268d

Citation:
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.
PDB ID: 2J1XDownload
MMDB ID: 53645
PDB Deposition Date: 2006/8/15
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 1.65  Å
Source Organism:
Similar Structures:
Biological Unit for 2J1X: monomeric; determined by author and by software (PQS)
Molecular Components in 2J1X
Label Count Molecule
Protein (1 molecule)
1
Cellular Tumor Antigen P53(Gene symbol: TP53)
Molecule annotation
Chemical (1 molecule)
1
1
* Click molecule labels to explore molecular sequence information.

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