8AXU
Small molecule stabilizer for ERalpha and 14-3-3 (1075297)
8AXU の概要
エントリーDOI | 10.2210/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 | Konstantinidou, M.,Visser, E.J.,Vandenboorn, E.M.F.,Sheng, C.,Jaishankar, P.,Overmans, M.J.A.M.,Dutta, S.,Neitz, J.,Renslo, A.,Ottmann, C.,Brunsveld, L.,Arkin, M. (登録日: 2022-09-01, 公開日: 2023-09-20, 最終更新日: 2023-10-04) |
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: 37676236DOI: 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
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