6Y4Q

Structure of a stapled peptide bound to MDM2

Summary for 6Y4Q

• Entry DOI: 10.2210/pdb6y4q/pdb
• Descriptor: E3 ubiquitin-protein ligase Mdm2, ACE-LEU-THR-PHE-GLY-GLU-TYR-TRP-ALA-GLN-LEU-ALA-SER, ~{N}-[(1-ethyl-1,2,3-triazol-4-yl)methyl]-~{N},5-dimethyl-4-[2-[2-methyl-5-[methyl-[(1-propyl-1,2,3-triazol-4-yl)methyl]carbamoyl]thiophen-3-yl]cyclopenten-1-yl]thiophene-2-carboxamide, ... (4 entities in total)
• Functional Keywords: mdm2, p53, stapled, ligase
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 25377.72

Authors

Pantelejevs, T.,Bakanovych, I. (deposition date: 2020-02-22, release date: 2020-05-20, Last modification date: 2024-11-06)

Primary citation

Strizhak, A.V.,Babii, O.,Afonin, S.,Bakanovich, I.,Pantelejevs, T.,Xu, W.,Fowler, E.,Eapen, R.,Sharma, K.,Platonov, M.O.,Hurmach, V.V.,Itzhaki, L.,Hyvonen, M.,Ulrich, A.S.,Spring, D.R.,Komarov, I.V.
Diarylethene moiety as an enthalpy-entropy switch: photoisomerizable stapled peptides for modulating p53/MDM2 interaction.
Org.Biomol.Chem., 18:5359-5369, 2020

PubMed 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.

PubMed: 32390036
DOI: 10.1039/d0ob00831a

Experimental method

X-RAY DIFFRACTION (1.63 Å)