8U7E

Structure of Sts-1 HP domain with rebamipide derivative

8U7E の概要

• エントリーDOI: 10.2210/pdb8u7e/pdb
• 関連するPDBエントリー: 8U5M
• 分子名称: Ubiquitin-associated and SH3 domain-containing protein B, N-(4-ethylbenzoyl)-3-(2-oxo-1,2-dihydroquinolin-4-yl)-L-alanine (3 entities in total)
• 機能のキーワード: sts-1, histidine phosphatase, inhibitor, ubash3b, tula-2, hydrolase-hydrolase inhibitor complex, hydrolase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 6
• 化学式量合計: 193679.68

構造登録者

Aziz, F.,Dey, R.,French, J.B. (登録日: 2023-09-15, 公開日: 2024-02-07, 最終更新日: 2024-02-21)

主引用文献

Aziz, F.,Reddy, K.,Fernandez Vega, V.,Dey, R.,Hicks, K.A.,Rao, S.,Jordan, L.O.,Smith, E.,Shumate, J.,Scampavia, L.,Carpino, N.,Spicer, T.P.,French, J.B.
Rebamipide and Derivatives are Potent, Selective Inhibitors of Histidine Phosphatase Activity of the Suppressor of T Cell Receptor Signaling Proteins.
J.Med.Chem., 67:1949-1960, 2024

PubMed Abstract: The suppressor of T cell receptor signaling (Sts) proteins are negative regulators of immune signaling. Genetic inactivation of these proteins leads to significant resistance to infection. From a 590,000 compound high-throughput screen, we identified the 2-()-quinolinone derivative, rebamipide, as a putative inhibitor of Sts phosphatase activity. Rebamipide, and a small library of derivatives, are competitive, selective inhibitors of Sts-1 with IC values from low to submicromolar. SAR analysis indicates that the quinolinone, the acid, and the amide moieties are all essential for activity. A crystal structure confirmed the SAR and reveals key interactions between this class of compound and the protein. Although rebamipide has poor cell permeability, we demonstrated that a liposomal preparation can inactivate the phosphatase activity of Sts-1 in cells. These studies demonstrate that Sts-1 enzyme activity can be pharmacologically inactivated and provide foundational tools and insights for the development of immune-enhancing therapies that target the Sts proteins.

PubMed: 38252624
DOI: 10.1021/acs.jmedchem.3c01763

実験手法

X-RAY DIFFRACTION (2.63 Å)