8U5M

Structure of Sts-1 HP domain with rebamipide

Summary for 8U5M

• Entry DOI: 10.2210/pdb8u5m/pdb
• Descriptor: Ubiquitin-associated and SH3 domain-containing protein B, Rebamipide (3 entities in total)
• Functional Keywords: sts-1, histidine phosphatase, inhibitor, ubash3b, tula-2, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 193698.86

Authors

Azia, F.,Dey, R.,French, J.B. (deposition date: 2023-09-12, release date: 2024-02-07, Last modification date: 2024-02-21)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.46 Å)