Journal
JOURNAL OF MOLECULAR BIOLOGY
Volume 385, Issue 1, Pages 11-21Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2008.10.053
Keywords
protein phosphatase 1; nodularin-R; tautomycin; crystal structure; molecular toxins
Categories
Funding
- National Research Service Award Fellow [F32NS054493]
- NIH [P20RR016457, R01NS056128]
- Manning Assistant Professor of Medical Science at Brown University
- National Institute of General Medical Sciences [GM-0080]
- The National Synchrotron Light Source
- Brookhaven National Laboratory
- U.S. Department of Energy [DE-AC02-98CH10886]
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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 angstrom and tautomycin at L70 angstrom 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. (C) 2008 Elsevier Ltd. All rights reserved.
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