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J Am Chem Soc. 2017 Dec 13;139(49):17703-17706. doi: 10.1021/jacs.7b09368. Epub 2017 Nov 28.

PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors.

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Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
Department of Biochemistry and Molecular Biology, University of South Alabama , Mobile, Alabama 36688, United States.
Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth , Lebanon, New Hampshire 03756, United States.
Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth , Lebanon, New Hampshire 03756, United States.


Selective inhibitors for each serine/threonine phosphatase (PPP) are essential to investigate the biological actions of PPPs and to guide drug development. Biologically diverse organisms (e.g., cyanobacteria, dinoflagellates, beetles) produce structurally distinct toxins that are catalytic inhibitors of PPPs. However, most toxins exhibit little selectivity, typically inhibiting multiple family members with similar potencies. Thus, the use of these toxins as chemical tools to study the relationship between individual PPPs and their biological substrates, and how disruptions in these relationships contributes to human disease, is severely limited. Here, we show that tautomycetin (TTN) is highly selective for a single PPP, protein phosphatase 1 (PP1/PPP1C). Our structure of the PP1:TTN complex reveals that PP1 selectivity is defined by a covalent bond between TTN and a PP1-specific cysteine residue, Cys127. Together, these data provide key molecular insights needed for the development of novel probes targeting single PPPs, especially PP1.

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