7AZ2

14-3-3 sigma with Pin1 binding site pS72 and covalently bound LvD1014

7AZ2 の概要

• エントリーDOI: 10.2210/pdb7az2/pdb
• 関連するPDBエントリー: 7AOG
• 分子名称: 14-3-3 protein sigma, Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1, 1-[4-methyl-2-(trifluoromethyl)phenyl]-2-phenyl-imidazole, ... (6 entities in total)
• 機能のキーワード: 1433, peptide binding protein, peptidyl-prolyl cis-trans isomerase nima-interacting 1
• 由来する生物種: Homo sapiens (Human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 30782.75

構造登録者

Wolter, M.,Dijck, L.v.,Ottmann, C. (登録日: 2020-11-14, 公開日: 2021-06-16, 最終更新日: 2024-10-23)

主引用文献

Cossar, P.J.,Wolter, M.,van Dijck, L.,Valenti, D.,Levy, L.M.,Ottmann, C.,Brunsveld, L.
Reversible Covalent Imine-Tethering for Selective Stabilization of 14-3-3 Hub Protein Interactions.
J.Am.Chem.Soc., 143:8454-8464, 2021

PubMed Abstract: The stabilization of protein complexes has emerged as a promising modality, expanding the number of entry points for novel therapeutic intervention. Targeting proteins that mediate protein-protein interactions (PPIs), such as hub proteins, is equally challenging and rewarding as they offer an intervention platform for a variety of diseases, due to their large interactome. 14-3-3 hub proteins bind phosphorylated motifs of their interaction partners in a conserved binding channel. The 14-3-3 PPI interface is consequently only diversified by its different interaction partners. Therefore, it is essential to consider, additionally to the potency, also the selectivity of stabilizer molecules. Targeting a lysine residue at the interface of the composite 14-3-3 complex, which can be targeted explicitly via aldimine-forming fragments, we studied the design of PPI stabilizers under consideration of potential selectivity. By applying cooperativity analysis of ternary complex formation, we developed a reversible covalent molecular glue for the 14-3-3/Pin1 interaction. This small fragment led to a more than 250-fold stabilization of the 14-3-3/Pin1 interaction by selective interfacing with a unique tryptophan in Pin1. This study illustrates how cooperative complex formation drives selective PPI stabilization. Further, it highlights how specific interactions within a hub proteins interactome can be stabilized over other interactions with a common binding motif.

PubMed: 34047554
DOI: 10.1021/jacs.1c03035

実験手法

X-RAY DIFFRACTION (1.081 Å)