6y4q

Publication Abstract from PubMed

Analogs of the known inhibitor (peptide pDI) of the p53/MDM2 protein-protein interaction are reported, which are stapled by linkers bearing a photoisomerizable diarylethene moiety. The corresponding photoisomers possess significantly different affinities to the p53-interacting domain of the human MDM2. Apparent dissociation constants are in the picomolar-to-low nanomolar range for those isomers with diarylethene in the "open" configuration, but up to eight times larger for the corresponding "closed" isomers. Spectroscopic, structural, and computational studies showed that the stapling linkers of the peptides contribute to their binding. Calorimetry revealed that the binding of the "closed" isomers is mostly enthalpy-driven, whereas the "open" photoforms bind to the protein stronger due to their increased binding entropy. The results suggest that conformational dynamics of the protein-peptide complexes may explain the differences in the thermodynamic profiles of the binding.

Diarylethene moiety as an enthalpy-entropy switch: photoisomerizable stapled peptides for modulating p53/MDM2 interaction.,Strizhak AV, Babii O, Afonin S, Bakanovich I, Pantelejevs T, Xu W, Fowler E, Eapen R, Sharma K, Platonov MO, Hurmach VV, Itzhaki L, Hyvonen M, Ulrich AS, Spring DR, Komarov IV Org Biomol Chem. 2020 May 11. doi: 10.1039/d0ob00831a. PMID:32390036^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.