Issue 28, 2020

Diarylethene moiety as an enthalpy-entropy switch: photoisomerizable stapled peptides for modulating p53/MDM2 interaction

Abstract

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.

Graphical abstract: Diarylethene moiety as an enthalpy-entropy switch: photoisomerizable stapled peptides for modulating p53/MDM2 interaction

Supplementary files

Article information

Article type
Paper
Submitted
24 Mar 2020
Accepted
24 Apr 2020
First published
11 May 2020
This article is Open Access
Creative Commons BY license

Org. Biomol. Chem., 2020,18, 5359-5369

Diarylethene moiety as an enthalpy-entropy switch: photoisomerizable stapled peptides for modulating p53/MDM2 interaction

A. V. Strizhak, O. Babii, S. Afonin, I. Bakanovich, T. Pantelejevs, W. Xu, E. Fowler, R. Eapen, K. Sharma, M. O. Platonov, V. V. Hurmach, L. Itzhaki, M. Hyvönen, A. S. Ulrich, D. R. Spring and I. V. Komarov, Org. Biomol. Chem., 2020, 18, 5359 DOI: 10.1039/D0OB00831A

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements