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8AXU

Small molecule stabilizer for ERalpha and 14-3-3 (1075297)

8AXU の概要
エントリーDOI10.2210/pdb8axu/pdb
分子名称14-3-3 protein sigma, Estrogen receptor, MAGNESIUM ION, ... (5 entities in total)
機能のキーワード14-3-3, eralpha, stabilizer, structural 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27642.76
構造登録者
主引用文献Konstantinidou, M.,Visser, E.J.,Vandenboorn, E.,Chen, S.,Jaishankar, P.,Overmans, M.,Dutta, S.,Neitz, R.J.,Renslo, A.R.,Ottmann, C.,Brunsveld, L.,Arkin, M.R.
Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3 sigma /ER alpha Protein-Protein Interaction from Nonselective Fragments.
J.Am.Chem.Soc., 145:20328-20343, 2023
Cited by
PubMed Abstract: The stabilization of protein-protein interactions (PPIs) has emerged as a promising strategy in chemical biology and drug discovery. The identification of suitable starting points for stabilizing native PPIs and their subsequent elaboration into selective and potent molecular glues lacks structure-guided optimization strategies. We have previously identified a disulfide fragment that stabilized the hub protein 14-3-3σ bound to several of its clients, including ERα and C-RAF. Here, we show the structure-based optimization of the nonselective fragment toward selective and highly potent small-molecule stabilizers of the 14-3-3σ/ERα complex. The more elaborated molecular glues, for example, show no stabilization of 14-3-3σ/C-RAF up to 150 μM compound. Orthogonal biophysical assays, including mass spectrometry and fluorescence anisotropy, were used to establish structure-activity relationships. The binding modes of 37 compounds were elucidated with X-ray crystallography, which further assisted the concomitant structure-guided optimization. By targeting specific amino acids in the 14-3-3σ/ERα interface and locking the conformation with a spirocycle, the optimized covalent stabilizer achieved potency, cooperativity, and selectivity similar to the natural product Fusicoccin-A. This case study showcases the value of addressing the structure, kinetics, and cooperativity for molecular glue development.
PubMed: 37676236
DOI: 10.1021/jacs.3c05161
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (1.6 Å)
構造検証レポート
Validation report summary of 8axu
検証レポート(詳細版)ダウンロードをダウンロード

227561

件を2024-11-20に公開中

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