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 Cited by 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: 38252624DOI: 10.1021/acs.jmedchem.3c01763 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (2.46 Å) |
Structure validation
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