||2X0W deposited: 2009-12-17 modified: 2010-02-23
||STRUCTURE OF THE P53 CORE DOMAIN MUTANT Y220C BOUND TO 5,6-DIMETHOXY-2-METHYLBENZOTHIAZOLE
||Basse, N., Fersht, A.R., Joerger, A.C., Kaar, J.L., Rutherford, T.J., Settanni, G.
||resolution 2.1 rfactor 0.1723 rfree 0.228
theoretical min: 0.21
|Related PDB Entries
The p53 cancer mutation Y220C induces formation of a cavity on the protein's surface that can accommodate stabilizing small molecules. We combined fragment screening and molecular dynamics to assess the druggability of p53-Y220C and map ligand interaction sites within the mutational cavity. Elucidation of the binding mode of fragment hits by crystallography yielded a clear picture of how a drug might dock in the cavity. Simulations that solvate the protein with isopropanol found additional sites that extend the druggable surface. Moreover, structural observations and simulation revealed the dynamic landscape of the cavity, which improves our understanding of the impact of the mutation on p53 stability. This underpins the importance of considering flexibility of the cavity in screening for optimized ligands. Our findings provide a blueprint for the design of effective drugs that rescue p53-Y220C.
Chem.Biol. 2010 Jan; 17(1):46-56 doi:10.1016/j.chembiol.2009.12.011
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.
Proc.Natl.Acad.Sci.USA 2006 Oct; 103(41):15056- doi:10.1073/PNAS.0607286103