9I72

14-3-3sigma binding to the ERa peptide and compound 10

これはPDB形式変換不可エントリーです。

9I72 の概要

• エントリーDOI: 10.2210/pdb9i72/pdb
• 分子名称: 14-3-3 protein sigma, Estrogen receptor, 2-chloranyl-~{N}-[4-(3-phenylazanylimidazo[1,2-a]pyridin-2-yl)phenyl]ethanamide, ... (7 entities in total)
• 機能のキーワード: 14-3-3, protein-protein interactions, stabilization, 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: 27753.42

構造登録者

Pennings, M.A.M.,Arkin, M.R. (登録日: 2025-01-31, 公開日: 2025-07-30)

主引用文献

Konstantinidou, M.,Zingiridis, M.,Pennings, M.A.M.,Fragkiadakis, M.,Virta, J.M.,Revalde, J.L.,Visser, E.J.,Ottmann, C.,Brunsveld, L.,Neochoritis, C.G.,Arkin, M.R.
Scaffold-hopping for molecular glues targeting the 14-3-3/ER alpha complex.
Nat Commun, 16:6467-6467, 2025

PubMed Abstract: Molecular glues, small molecules that bind cooperatively at a protein-protein interface, have emerged as powerful modalities for the modulation of protein-protein interactions (PPIs) and "undruggable" targets. The systematic identification of new chemical matter with a molecular glue mechanism of action remains a significant challenge in drug discovery. Here, we present a scaffold hopping approach, using as a starting point our previously developed molecular glues for the native 14-3-3/estrogen receptor alpha (ERα) complex. The novel, computationally designed scaffold is based on the Groebke-Blackburn-Bienaymé multi-component reaction (MCR), leading to drug-like analogs with multiple points of variation, thus enabling the rapid derivatization and optimization of the scaffold. Structure-activity relationships (SAR) are developed using orthogonal biophysical assays, such as intact mass spectrometry, TR-FRET and SPR. Rational structure-guided optimization is facilitated by multiple crystal structures of ternary complexes with the glues, 14-3-3 and phospho-peptides mimicking the highly disordered C-terminus of ERα. Cellular stabilization of 14-3-3/ERα for the most potent analogs is confirmed using a NanoBRET assay with full-length proteins in live cells. Our approach highlights the potential of MCR chemistry, combined with scaffold hopping, to drive the development and optimization of unprecedented molecular glue scaffolds.

PubMed: 40659654
DOI: 10.1038/s41467-025-61176-4

実験手法

X-RAY DIFFRACTION (1.35 Å)