6GGB

p53 cancer mutant Y220C in complex with small-molecule stabilizer PK9318

Summary for 6GGB

• Entry DOI: 10.2210/pdb6ggb/pdb
• Descriptor: Cellular tumor antigen p53, ZINC ION, [9-ethyl-7-(4-methylthiophen-2-yl)carbazol-3-yl]methyl-methyl-azanium, ... (7 entities in total)
• Functional Keywords: p53, transcription factor, tumor supressor, cancer therapy, oncogenic mutant, protein misfolding, small-molecule stabilizer, molecular chaperone, dna binding protein
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 50255.88

Authors

Joerger, A.C.,Bauer, M.R. (deposition date: 2018-05-03, release date: 2019-05-22, Last modification date: 2024-01-17)

Primary citation

Bauer, M.R.,Jones, R.N.,Tareque, R.K.,Springett, B.,Dingler, F.A.,Verduci, L.,Patel, K.J.,Fersht, A.R.,Joerger, A.C.,Spencer, J.
A structure-guided molecular chaperone approach for restoring the transcriptional activity of the p53 cancer mutant Y220C.
Future Med Chem, 11:2491-2504, 2019

PubMed Abstract: The p53 cancer mutation Y220C creates a conformationally unstable protein with a unique elongated surface crevice that can be targeted by molecular chaperones. We report the structure-guided optimization of the carbazole-based stabilizer PK083.  Biophysical, cellular and x-ray crystallographic techniques have been employed to elucidate the mode of action of the carbazole scaffolds.  Targeting an unoccupied subsite of the surface crevice with heterocycle-substituted PK083 analogs resulted in a 70-fold affinity increase to single-digit micromolar levels, increased thermal stability and decreased rate of aggregation of the mutant protein. PK9318, one of the most potent binders, restored p53 signaling in the liver cancer cell line HUH-7 with homozygous Y220C mutation. The p53-Y220C mutant is an excellent paradigm for the development of mutant p53 rescue drugs via protein stabilization. Similar rescue strategies may be applicable to other cavity-creating p53 cancer mutations.

PubMed: 31633398
DOI: 10.4155/fmc-2019-0181

Experimental method

X-RAY DIFFRACTION (1.32 Å)