Activation of protein phosphatase 1 by a small molecule designed to bind to the enzyme's regulatory site.
The activity of protein phosphatase 1 (PP1), a serine-threonine phosphatase that participates ubiquitously in cellular signaling, is controlled by a wide variety of regulatory proteins that interact with PP1 at an allosteric regulatory site that recognizes a "loose" consensus sequence (usually designated as RVXF) found in all such regulatory proteins. Peptides containing the regulatory consensus sequence have been found to recapitulate the binding and PP1 activity modulation of the regulatory proteins, suggesting that it might be possible to design small-molecule surrogates that activate PP1 rather than inhibiting it. This prospect constitutes a largely unexplored way of controlling signaling pathways that could be functionally complementary to the much more extensively explored stratagem of kinase inhibition. Based on these principles, we have designed a microcystin analog that activates PP1.
Tappan
Erin
E
Department of Chemistry, University of California, Irvine, Irvine, CA 92697, USA.
Chamberlin
A Richard
AR
D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site; D000595:Amino Acid Sequence; D000818:Animals; D040761:Biomimetic Materials / Q000737:chemistry / Q000378:metabolism; D016384:Consensus Sequence; D015195:Drug Design; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D052998:Microcystins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology*; D008969:Molecular Sequence Data; D054645:Protein Phosphatase 1 / Q000737:chemistry* / Q000378:metabolism*; D011817:Rabbits
D052998:Microcystins; C078588:microcystin; D054645:Protein Phosphatase 1