The Lys-Specific Molecular Tweezer, CLR01, Modulates Aggregation of the Mutant p53 DNA Binding Domain and Inhibits Its Toxicity.

摘要: The tumor suppressor p53 plays a unique role as central hub of numerous cell proliferation and apoptotic pathways, its malfunction due to mutations is major cause various malignancies. Therefore, it serves an attractive target for developing novel anticancer therapeutics. Because intrinsically unstable DNA binding domain, unfolds rapidly at physiological temperature. Certain mutants shift the equilibrium toward unfolded state yield high-molecular weight, nonfunctional, cytotoxic β-sheet-rich aggregates that share tinctorial conformational similarities with amyloid deposits found in protein misfolding diseases. Here, we examined effect assembly modulator, lysine (Lys)-specific molecular tweezer, CLR01, on different aggregation stages misfolded mutant vitro cytotoxicity resulting culture. We CLR01 induced rapid formation β-sheet-rich, intermediate-size yet inhibited further reduced aggregates. Our data suggest modulators, such could prevent toxic