9SAC

14-3-3sigma protein binding to the ChREBP peptide and macrocycle 3

これはPDB形式変換不可エントリーです。

9SAC の概要

• エントリーDOI: 10.2210/pdb9sac/pdb
• 分子名称: 14-3-3 protein sigma, Carbohydrate-responsive element-binding protein, 5,6-DIHYDRO-BENZO[H]CINNOLIN-3-YLAMINE, ... (4 entities in total)
• 機能のキーワード: protein-peptide interaction, macrocyclic peptides, protein binding
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 28897.44

構造登録者

Pennings, M.A.M.,van den Bosch, M.A.W.,Brunsveld, L. (登録日: 2025-08-07, 公開日: 2026-02-11, 最終更新日: 2026-02-18)

主引用文献

Pennings, M.A.M.,van den Bosch, M.A.W.,Oberheide, A.,Verhoef, C.J.A.,Ottmann, C.,Markvoort, A.J.,Miley, G.P.,Brunsveld, L.
Macrocyclic Molecular Glues for the 14-3-3/ChREBP Interaction: Affinity and Cooperativity in an Inverse Relationship.
Angew.Chem.Int.Ed.Engl., 65:e21678-e21678, 2026

PubMed Abstract: Molecular glues (MGs) stabilize protein-protein interactions (PPIs) by simultaneously binding two or more proteins at their composite interface. Macrocycles present attractive properties as MGs, including large contact surfaces to address the often flat and undefined composite PPI interfaces, but their structure-based design has remained intangible. We have designed peptidomimetic macrocycles capable of enhancing the PPI between 14-3-3 and the carbohydrate response element binding protein (ChREBP), a regulatory transcription factor. Biophysical characterization of these MGs revealed the importance of optimized linker length, displaying a reduced entropic cost compared to the linear counterparts, while preserving key contacts with 14-3-3. Binding assays demonstrated that the macrocycles selectively and cooperatively stabilized the 14-3-3/ChREBP complex, with an intriguing inverse relationship between intrinsic binding affinity to 14-3-3 and cooperativity in PPI stabilization. Ternary co-crystal structures of the macrocycles binding at the composite 14-3-3/ChREBP interface provided a molecular rationale for the affinity and cooperativity differences. Overall, this study highlights structural, kinetic, and thermodynamic features that guide effective macrocyclic MG design and brings forward the crucial interplay of affinity and cooperativity in stabilizing PPIs.

PubMed: 41414041
DOI: 10.1002/anie.202521678

実験手法

X-RAY DIFFRACTION (2.5 Å)