8p0d
From Proteopedia
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<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8p0d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8p0d OCA], [https://pdbe.org/8p0d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8p0d RCSB], [https://www.ebi.ac.uk/pdbsum/8p0d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8p0d ProSAT]</span></td></tr> | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=8p0d FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8p0d OCA], [https://pdbe.org/8p0d PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8p0d RCSB], [https://www.ebi.ac.uk/pdbsum/8p0d PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8p0d ProSAT]</span></td></tr> | ||
</table> | </table> | ||
| - | == | + | <div style="background-color:#fffaf0;"> |
| - | + | == Publication Abstract from PubMed == | |
| + | 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 14-3-3sigma isoform controls MDM2 cellular localization and stability to inhibit its activity. Therefore, small molecule stabilization of the 14-3-3sigma/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 14-3-3sigma 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 14-3-3sigma. 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 14-3-3sigma-MDM2 interaction is amenable to small molecule stabilization. The natural product fusicoccin A forms a ternary complex with a 14-3-3sigma dimer and an MDM2 di-phosphorylated peptide resulting in the stabilization of the 14-3-3sigma/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. | ||
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| + | Characterizing the protein-protein interaction between MDM2 and 14-3-3sigma; proof of concept for small molecule stabilization.,Ward JA, Romartinez-Alonso B, Kay DF, Bellamy-Carter J, Thurairajah B, Basran J, Kwon H, Leney AC, Macip S, Roversi P, Muskett FW, Doveston RG J Biol Chem. 2024 Feb;300(2):105651. doi: 10.1016/j.jbc.2024.105651. Epub 2024 , Jan 16. PMID:38237679<ref>PMID:38237679</ref> | ||
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| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
| + | </div> | ||
| + | <div class="pdbe-citations 8p0d" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
Current revision
Human 14-3-3 sigma in complex with human MDM2 peptide
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