Insights into Allosteric Mechanisms of the Lung-Enriched p53 Mutants V157F and R158L.

Lung cancer is a leading fatal malignancy in humans. p53 mutants exhibit not only loss of tumor suppressor capability but also oncogenic gain-of-function, contributing to lung cancer initiation, progression and therapeutic resistance. Research shows that p53 mutants V157F and R158L occur with high frequency in lung squamous cell carcinomas. Revealing their conformational dynamics is critical for developing novel lung therapies. Here, we used all-atom molecular dynamics (MD) simulations to investigate the effect of V157F and R158L substitutions on the structural properties of the p53 core domain (p53C). Compared to wild-type (WT) p53C, both V157F and R158L mutants display slightly lesser ß-sheet structure, larger radius of gyration, larger volume and larger exposed surface area, showing aggregation-prone structural characteristics. The aggregation-prone fragments (residues 249-267 and 268-282) of two mutants are more exposed to water solution than that of WT p53C. V157F and R158L mutation sites can affect the conformation switch of loop 1 through long-range associations. Simulations also reveal that the local structure and conformation around the V157F and R158L mutation sites are in a dynamic equilibrium between the misfolded and properly folded conformations. These results provide molecular mechanistic insights into allosteric mechanisms of the lung-enriched p53 mutants.

Copper(ii)-containing tungstotellurates(vi): syntheses, structures and their catalytic performances in selective oxidation of thioethers.

We report the syntheses and structures of two new copper(ii)-containing tungstotellurates(vi) Na12[TeVI 2W8O38Cu2(H2O)2]·7H2O (Te2W8Cu2) and Na6[TeVIW6O24Cu(NH2CH2CO2)2]·6H2O (TeW6Cu). The two compounds were synthesized by a simple one-pot method and characterized by single-crystal X-ray diffraction (XRD), powder XRD, FT-IR spectroscopy, elemental analysis, and thermogravimetric analysis in the solid state. Furthermore, their catalytic properties for the selective oxidation of thioethers were also studied systematically. The catalytic experiment results indicate that the tungstotellurate(vi) Te2W8Cu2 is an effective heterogeneous catalyst for the selective oxidation of thioethers to sulfoxides or sulfones by an H2O2 oxidant at room temperature. Under the ambient conditions, Te2W8Cu2 can convert 99% of methyl(phenyl)sulfane to sulfoxides or sulfones with 96% or 99% selectivity, respectively, and the utilization rate of H2O2 is up to 80%. Furthermore, Te2W8Cu2 as a heterogeneous catalyst is stable in the reaction and could be reused at least five cycles with conserved activity.