6TL3

Crystal structure of an Estrogen Receptor alpha 8-mer phosphopeptide in complex with 14-3-3sigma stabilized by a Pyrrolidone1 derivative

6TL3 の概要

• エントリーDOI: 10.2210/pdb6tl3/pdb
• 関連するPDBエントリー: 6TJM
• 分子名称: 14-3-3 protein sigma, Estrogen receptor, 5-[(2~{S},3~{R})-3-[(~{R})-azanyl(phenyl)methyl]-2-(4-nitrophenyl)-4,5-bis(oxidanylidene)pyrrolidin-1-yl]-2-oxidanyl-benzoic acid, ... (4 entities in total)
• 機能のキーワード: estrogen receptor, 14-3-3, ppi, stabiliser, complex, signaling 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: 27915.20

構造登録者

Andrei, S.A.,Bosica, F.,Ottmann, C.,O'Mahony, G. (登録日: 2019-11-30, 公開日: 2020-04-29, 最終更新日: 2024-10-16)

主引用文献

Bosica, F.,Andrei, S.A.,Neves, J.F.,Brandt, P.,Gunnarsson, A.,Landrieu, I.,Ottmann, C.,O'Mahony, G.
Design of Drug-Like Protein-Protein Interaction Stabilizers Guided By Chelation-Controlled Bioactive Conformation Stabilization.
Chemistry, 26:7131-7139, 2020

PubMed Abstract: Protein-protein interactions (PPIs) of 14-3-3 proteins are a model system for studying PPI stabilization. The complex natural product Fusicoccin A stabilizes many 14-3-3 PPIs but is not amenable for use in SAR studies, motivating the search for more drug-like chemical matter. However, drug-like 14-3-3 PPI stabilizers enabling such studies have remained elusive. An X-ray crystal structure of a PPI in complex with an extremely low potency stabilizer uncovered an unexpected non-protein interacting, ligand-chelated Mg leading to the discovery of metal-ion-dependent 14-3-3 PPI stabilization potency. This originates from a novel chelation-controlled bioactive conformation stabilization effect. Metal chelation has been associated with pan-assay interference compounds (PAINS) and frequent hitter behavior, but chelation can evidently also lead to true potency gains and find use as a medicinal chemistry strategy to guide compound optimization. To demonstrate this, we exploited the effect to design the first potent, selective, and drug-like 14-3-3 PPI stabilizers.

PubMed: 32255539
DOI: 10.1002/chem.202001608

実験手法

X-RAY DIFFRACTION (2.455 Å)