6ALZ

Crystal structure of Protein Phosphatase 1 bound to the natural inhibitor Tautomycetin

Summary for 6ALZ

• Entry DOI: 10.2210/pdb6alz/pdb
• Descriptor: Serine/threonine-protein phosphatase PP1-alpha catalytic subunit, MANGANESE (II) ION, (2Z)-2-[(1R)-3-{[(2R,3S,4R,7S,8S,11S,13R,16E)-17-ethyl-4,8-dihydroxy-3,7,11,13-tetramethyl-6,15-dioxononadeca-16,18-dien-2-yl]oxy}-1-hydroxy-3-oxopropyl]-3-methylbut-2-enedioic acid, ... (6 entities in total)
• Functional Keywords: inhibitor, complex, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 2
• Total formula weight: 70013.51

Authors

Choy, M.S.,Peti, W.,Page, R. (deposition date: 2017-08-08, release date: 2017-11-29, Last modification date: 2024-10-30)

Primary citation

Choy, M.S.,Swingle, M.,D'Arcy, B.,Abney, K.,Rusin, S.F.,Kettenbach, A.N.,Page, R.,Honkanen, R.E.,Peti, W.
PP1:Tautomycetin Complex Reveals a Path toward the Development of PP1-Specific Inhibitors.
J. Am. Chem. Soc., 139:17703-17706, 2017

PubMed Abstract: 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.

PubMed: 29156132
DOI: 10.1021/jacs.7b09368

Experimental method

X-RAY DIFFRACTION (2.208 Å)