7NK5

14-3-3 sigma with RelA/p65 binding site pS45 and covalently bound TCF521-124

7NK5 の概要

• エントリーDOI: 10.2210/pdb7nk5/pdb
• 関連するPDBエントリー: 6QHL
• 分子名称: 14-3-3 protein sigma, Transcription factor p65, 1-(4-methylphenyl)sulfonyl-4-(2-methylpropyl)piperazine, ... (6 entities in total)
• 機能のキーワード: benzaldehyde, covalent fragment, p65, 1433, rela, peptide binding protein
• 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: 30067.55

構造登録者

Wolter, M.,Ottmann, C. (登録日: 2021-02-17, 公開日: 2021-06-09, 最終更新日: 2024-11-20)

主引用文献

Wolter, M.,Valenti, D.,Cossar, P.J.,Hristeva, S.,Levy, L.M.,Genski, T.,Hoffmann, T.,Brunsveld, L.,Tzalis, D.,Ottmann, C.
An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-kappa B-Utilizing a Reversible Covalent Tethering Approach.
J.Med.Chem., 64:8423-8436, 2021

PubMed Abstract: Protein-protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein-protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.

PubMed: 34076416
DOI: 10.1021/acs.jmedchem.1c00401

実験手法

X-RAY DIFFRACTION (1.4 Å)