Journal
ORGANIC & BIOMOLECULAR CHEMISTRY
Volume 18, Issue 28, Pages 5359-5369Publisher
ROYAL SOC CHEMISTRY
DOI: 10.1039/d0ob00831a
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Funding
- EU [690973]
- DFG [GRK 2039]
- BMBF-VIP +
- Medical Research Council (UK)
- X-ray Crystallographic and Biophysical Research Facility at the Department of Biochemistry, University of Cambridge
- Marie Curie Actions (MSCA) [690973] Funding Source: Marie Curie Actions (MSCA)
- MRC [1800792] Funding Source: UKRI
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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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