8AV0

small molecule stabilizer (compound 1) for C-RAF pS259 and 14-3-3

8AV0 の概要

• エントリーDOI: 10.2210/pdb8av0/pdb
• 分子名称: 14-3-3 protein sigma, RAF proto-oncogene serine/threonine-protein kinase, CHLORIDE ION, ... (6 entities in total)
• 機能のキーワード: ppi stabilization, 14-3-3, c-raf, disulfide tethering, surfactant 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: 28152.37

構造登録者

Visser, E.J.,Sijbesma, E.,Ottmann, C. (登録日: 2022-08-26, 公開日: 2023-04-26, 最終更新日: 2024-11-06)

主引用文献

Kenanova, D.N.,Visser, E.J.,Virta, J.M.,Sijbesma, E.,Centorrino, F.,Vickery, H.R.,Zhong, M.,Neitz, R.J.,Brunsveld, L.,Ottmann, C.,Arkin, M.R.
A Systematic Approach to the Discovery of Protein-Protein Interaction Stabilizers.
Acs Cent.Sci., 9:937-946, 2023

PubMed Abstract: Dysregulation of protein-protein interactions (PPIs) commonly leads to disease. PPI stabilization has only recently been systematically explored for drug discovery despite being a powerful approach to selectively target intrinsically disordered proteins and hub proteins, like 14-3-3, with multiple interaction partners. Disulfide tethering is a site-directed fragment-based drug discovery (FBDD) methodology for identifying reversibly covalent small molecules. We explored the scope of disulfide tethering for the discovery of selective PPI stabilizers (molecular glues) using the hub protein 14-3-3σ. We screened complexes of 14-3-3 with 5 biologically and structurally diverse phosphopeptides derived from the 14-3-3 client proteins ERα, FOXO1, C-RAF, USP8, and SOS1. Stabilizing fragments were found for 4/5 client complexes. Structural elucidation of these complexes revealed the ability of some peptides to conformationally adapt to make productive interactions with the tethered fragments. We validated eight fragment stabilizers, six of which showed selectivity for one phosphopeptide client, and structurally characterized two nonselective hits and four fragments that selectively stabilized C-RAF or FOXO1. The most efficacious fragment increased 14-3-3σ/C-RAF phosphopeptide affinity by 430-fold. Disulfide tethering to the wildtype C38 in 14-3-3σ provided diverse structures for future optimization of 14-3-3/client stabilizers and highlighted a systematic method to discover molecular glues.

PubMed: 37252362
DOI: 10.1021/acscentsci.2c01449

実験手法

X-RAY DIFFRACTION (1.5 Å)