5WDI

Structure of Human Sts-2 histidine phosphatase domain

Summary for 5WDI

• Entry DOI: 10.2210/pdb5wdi/pdb
• Descriptor: Ubiquitin-associated and SH3 domain-containing protein A, SULFATE ION (3 entities in total)
• Functional Keywords: t-cell receptor, histidine phosphatase, protein tyrosine phosphatase, zap-70, hydrolase
• Biological source: Homo sapiens (Human)
• Cellular location: Cytoplasm: P57075
• Total number of polymer chains: 2
• Total formula weight: 60142.97

Authors

Zhou, W.,Yin, Y.,Weinheimer, A.W.,Kaur, N.,Carpino, N.,French, J.B. (deposition date: 2017-07-05, release date: 2017-08-16, Last modification date: 2023-10-04)

Primary citation

Zhou, W.,Yin, Y.,Weinheimer, A.S.,Kaur, N.,Carpino, N.,French, J.B.
Structural and Functional Characterization of the Histidine Phosphatase Domains of Human Sts-1 and Sts-2.
Biochemistry, 56:4637-4645, 2017

PubMed Abstract: The suppressor of T cell signaling (Sts) proteins, Sts-1 and Sts-2, are homologous phosphatases that negatively regulate signaling pathways downstream of the T cell receptor. Functional inactivation of Sts-1 and Sts-2 in a murine model leads to resistance to systemic infection by the opportunistic pathogen, Candida albicans. This suggests that modulation of the host immune response by inhibiting Sts function may be a viable strategy for treating these deadly fungal pathogen infections. To better understand the molecular determinants of function and structure, we characterized the structure and steady-state kinetics of the histidine phosphatase domains of human Sts-1 (Sts-1) and Sts-2 (Sts-2). We determined the X-ray crystal structures of unliganded Sts-1 and Sts-1 in complex with sulfate to 2.5 and 1.9 Å, respectively, and the structure of Sts-2 with sulfate to 2.4 Å. The steady-state kinetic analysis shows, as expected, that Sts-1 has a phosphatase activity significantly higher than that of Sts-2 and that the human and mouse proteins behave similarly. In addition, comparison of the phosphatase activity of full-length Sts-1 protein to Sts-1 reveals similar kinetics, indicating that Sts-1 is a functional surrogate for the native protein. We also tested known phosphatase inhibitors and determined that the SHP-1 inhibitor, PHPS1, is a potent inhibitor of Sts-1 (K = 1.05 ± 0.15 μM). Finally, we demonstrated that human Sts-1 has robust phosphatase activity against the substrate, Zap-70, in a cell-based assay. Collectively, these data suggest that the human Sts proteins are druggable targets and provide a structural basis for future drug development efforts.

PubMed: 28759203
DOI: 10.1021/acs.biochem.7b00638

Experimental method

X-RAY DIFFRACTION (2.43 Å)