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

Strizhak, Alexander V.; Babii, Oleg; Afonin, Sergii; Bakanovich, Iuliia; Pantelejevs, Teodors; Xu, Wenshu; Fowler, Elaine; Eapen, Rohan; Sharma, Krishna; Platonov, Maxim O.; Hurmach, Vasyl V.; Itzhaki, Laura; Hyvönen, Marko; Ulrich, Anne S.; Spring, David R.; Komarov, Igor V.

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.

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Verlagsausgabe §
DOI: 10.5445/IR/1000123266
Veröffentlicht am 03.09.2020
Originalveröffentlichung
DOI: 10.1039/d0ob00831a
Scopus
Zitationen: 1
Web of Science
Zitationen: 2
Dimensions
Zitationen: 2
Cover der Publikation
Zugehörige Institution(en) am KIT Institut für Biologische Grenzflächen (IBG)
Institut für Organische Chemie (IOC)
Publikationstyp Zeitschriftenaufsatz
Publikationsjahr 2020
Sprache Englisch
Identifikator ISSN: 1477-0520, 1477-0539
KITopen-ID: 1000123266
HGF-Programm 47.02.02 (POF III, LK 01) Zellpopul.auf Biofunk.Oberflächen IBG-2
Erschienen in Organic & biomolecular chemistry
Verlag Royal Society of Chemistry (RSC)
Band 18
Heft 28
Seiten 5359–5369
Vorab online veröffentlicht am 11.05.2020
Nachgewiesen in Dimensions
Web of Science
Scopus
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