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Instruments / Technical Area	Publication Details	Published	Actions
I04-Macromolecular Crystallography	Characterizing the protein–protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization Jake A. Ward , Beatriz Romartinez-Alonso , Danielle F. Kay , Jeddidiah Bellamy-Carter , Bethany Thurairajah , Jaswir Basran , Hanna Kwon , Aneika C. Leney , Salvador Macip , Pietro Roversi , Frederick W. Muskett , Richard G. Doveston Journal Of Biological Chemistry 300 DOI: 10.1016/j.jbc.2024.105651 Diamond Proposal Number(s): [26803] Open Access Show Abstract ▼ Abstract: Mouse Double Minute 2 (MDM2) is a key negative regulator of the tumor suppressor protein p53. MDM2 overexpression occurs in many types of cancer and results in the suppression of WT p53. The 14-3-3 family of adaptor proteins are known to bind MDM2 and the 14-3-3σ isoform controls MDM2 cellular localization and stability to inhibit its activity. Therefore, small molecule stabilization of the 14-3-3σ/MDM2 protein–protein interaction (PPI) is a potential therapeutic strategy for the treatment of cancer. Here, we provide a detailed biophysical and structural characterization of the phosphorylation-dependent interaction between 14-3-3σ and peptides that mimic the 14-3-3 binding motifs within MDM2. The data show that di-phosphorylation of MDM2 at S166 and S186 is essential for high affinity 14-3-3 binding and that the binary complex formed involves one MDM2 di-phosphorylated peptide bound to a dimer of 14-3-3σ. However, the two phosphorylation sites do not simultaneously interact so as to bridge the 14-3-3 dimer in a ‘multivalent’ fashion. Instead, the two phosphorylated MDM2 motifs ‘rock’ between the two binding grooves of the dimer, which is unusual in the context of 14-3-3 proteins. In addition, we show that the 14-3-3σ–MDM2 interaction is amenable to small molecule stabilization. The natural product fusicoccin A forms a ternary complex with a 14-3-3σ dimer and an MDM2 di-phosphorylated peptide resulting in the stabilization of the 14-3-3σ/MDM2 PPI. This work serves as a proof-of-concept of the drugability of the 14-3-3/MDM2 PPI and paves the way toward the development of more selective and efficacious small molecule stabilizers.	Feb 2024

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I04-Macromolecular Crystallography

Characterizing the protein–protein interaction between MDM2 and 14-3-3σ; proof of concept for small molecule stabilization