PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors
| Autor: | Kevin A Abney, Arminja N. Kettenbach, Scott F. Rusin, Mark R. Swingle, Rebecca Page, Brandon M. D'Arcy, Wolfgang Peti, Richard E. Honkanen, Meng S. Choy |
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| Rok vydání: | 2017 |
| Předmět: |
Models
Molecular 0301 basic medicine Biochemistry Article Catalysis Substrate Specificity Serine 03 medical and health sciences Residue (chemistry) 0302 clinical medicine Colloid and Surface Chemistry Protein Phosphatase 1 Humans Amino Acid Sequence Enzyme Inhibitors Furans Peptide sequence Chemistry Protein phosphatase 1 General Chemistry Tautomycetin Lipids 030104 developmental biology Drug development Covalent bond 030217 neurology & neurosurgery Cysteine |
| Zdroj: | Journal of the American Chemical Society. 139:17703-17706 |
| ISSN: | 1520-5126 0002-7863 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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