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PDBsum entry 3e7b
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References listed in PDB file
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Key reference
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Title
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Crystal structures of protein phosphatase-1 bound to nodularin-R and tautomycin: a novel scaffold for structure-Based drug design of serine/threonine phosphatase inhibitors.
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Authors
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M.S.Kelker,
R.Page,
W.Peti.
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Ref.
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J Mol Biol, 2009,
385,
11-21.
[DOI no: ]
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PubMed id
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Abstract
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Protein phosphatase 1 occurs in all tissues and regulates many pathways, ranging
from cell-cycle progression to carbohydrate metabolism. Many naturally
occurring, molecular toxins modulate PP1 activity, though the exact mechanism of
this differential regulation is not understood. A detailed elucidation of these
interactions is crucial for understanding the cellular basis of phosphatase
function and signaling pathways but, more importantly, they can serve as the
basis for highly specific therapeutics, e.g. against cancer. We report the
crystal structures of PP1 in complex with nodularin-R at 1.63 A and tautomycin
at 1.70 A resolution. The PP1:nodularin-R complex was used to demonstrate the
utility of our improved PP1 production technique, which produces highly active,
soluble PP1. Tautomycin is one of the few toxins that reportedly preferentially
binds PP1>PP2A. Therefore, the PP1:tautomycin structure is the first complex
structure with a toxin with preferred PP1 specificity. Furthermore, since
tautomycin is a linear non-peptide-based toxin, our reported structure will aid
the design of lead compounds for novel PP1-specific pharmaceuticals.
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Figure 1.
Fig. 1. Structures of nodularin-R (a), tautomycin (b),
tautomycetin (c) and cantharidin (d). Important interaction
sites with PP1 identified in this study are highlighted. An
asterisk marks the critical OH group in tautomycin. Details are
given in the text.
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Figure 4.
Fig. 4. PP1: cantharidin model. (a) Hydrogen bond interaction
network on cantharidin and the PP1 active site. PP1 residues
Y272, R221, and R96 make critical stabilizing interactions. (b)
Surface representation of the PP1:canthardin model. Four surface
pockets that can potentially be used to tether cantharidin-based
inhibitors on PP1 are highlighted.
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The above figures are
reprinted
from an Open Access publication published by Elsevier:
J Mol Biol
(2009,
385,
11-21)
copyright 2009.
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