4ja7

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== Publication Abstract from PubMed ==
== Publication Abstract from PubMed ==
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Protein phosphatase 5 (PP5) is an evolutionary conserved serine/threonine phosphatase. Its dephosphorylation activity modulates a diverse set of cellular factors including protein kinases and the microtubule-associated tau protein involved in neurodegenerative disorders. It is auto-regulated by its heat-shock protein (Hsp90)-interacting tetratricopeptide repeat (TPR) domain and its C-terminal alpha-helix. In the present study, we report the identification of five specific PP5 activators [PP5 small-molecule activators (P5SAs)] that enhance the phosphatase activity up to 8-fold. The compounds are allosteric modulators accelerating efficiently the turnover rate of PP5, but do barely affect substrate binding or the interaction between PP5 and the chaperone Hsp90. Enzymatic studies imply that the compounds bind to the phosphatase domain of PP5. For the most promising compound crystallographic comparisons of the apo PP5 and the PP5-P5SA-2 complex indicate a relaxation of the auto-inhibited state of PP5. Residual electron density and mutation analyses in PP5 suggest activator binding to a pocket in the phosphatase/TPR domain interface, which may exert regulatory functions. These compounds thus may expose regulatory mechanisms in the PP5 enzyme and serve to develop optimized activators based on these scaffolds.
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Protein phosphatase 5 (PP5) is an evolutionary conserved serine/threonine phosphatase that is autoregulated by its Hsp90-interacting tetratricopeptide repeat (TPR) domain and its C-terminal alphahelix. PP5-catalyzed dephosphorylation modulates a diverse set of cellular factors including protein kinases and the microtubule-associated tau-protein involved in neurodegenerative disorders. Here, we report the identification of five specific PP5 activators (P5SAs) that enhance the phosphatase activity up to 8-fold. The compounds are allosteric modulators accelerating exclusively the turnover rate of PP5, but do not affect substrate binding or the interaction between PP5 and the chaperone Hsp90. Functional studies imply a binding site in the phosphatase domain and crystallographic comparisons of the apo PP5 and the PP5:P5SA-2 complex indicate a relaxation of the autoinhibited state of PP5 upon activator binding to the phosphatase-TPR domain interface. Mutations in this site suppress the activatory potential of the ligands. Thus, these compounds may be able to target a regulatory pocket at the domain interface of the PP5 enzyme and serve as a starting point to develop optimized activators based on these scaffolds.
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Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism.,Haslbeck V, Drazic A, Eckl JM, Alte F, Helmuth M, Popowicz G, Schmidt W, Braun F, Weiwad M, Fischer G, Gemmecker G, Sattler M, Striggow F, Groll M, Richter K Biosci Rep. 2015 Apr 20;35(3). pii: e00210. doi: 10.1042/BSR20150042. PMID:26182372<ref>PMID:26182372</ref>
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Selective activators of protein phosphatase 5 target the autoinhibitory mechanism.,Haslbeck V, Drazic A, Eckl JM, Alte F, Helmuth M, Popowicz G, Schmidt W, Braun F, Weiwad M, Fischer G, Gemmecker G, Sattler M, Striggow F, Groll M, Richter K Biosci Rep. 2015 Apr 20. PMID:25892015<ref>PMID:25892015</ref>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

Revision as of 09:14, 10 February 2016

Rat PP5 co-crystallized with P5SA-2

4ja7, resolution 2.00Å

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