8P0D

Human 14-3-3 sigma in complex with human MDM2 peptide

Summary for 8P0D

• Entry DOI: 10.2210/pdb8p0d/pdb
• Related: 6YR6
• Descriptor: 14-3-3 protein sigma, E3 ubiquitin-protein ligase Mdm2, GLYCEROL, ... (7 entities in total)
• Functional Keywords: signaling protein-peptide complex, protein binding
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 33671.32

Authors

Roversi, P.,Ward, J.,Doveston, R.,Kwon, H.,Romartinez Alonso, B. (deposition date: 2023-05-10, release date: 2024-02-21, Last modification date: 2024-10-16)

Primary citation

Ward, J.A.,Romartinez-Alonso, B.,Kay, D.F.,Bellamy-Carter, J.,Thurairajah, B.,Basran, J.,Kwon, H.,Leney, A.C.,Macip, S.,Roversi, P.,Muskett, F.W.,Doveston, R.G.
Characterizing the protein-protein interaction between MDM2 and 14-3-3 sigma ; proof of concept for small molecule stabilization.
J.Biol.Chem., 300:105651-105651, 2024

PubMed 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.

PubMed: 38237679
DOI: 10.1016/j.jbc.2024.105651

Experimental method

X-RAY DIFFRACTION (1.31 Å)