4JA7

Rat PP5 co-crystallized with P5SA-2

4JA7 の概要

• エントリーDOI: 10.2210/pdb4ja7/pdb
• 関連するPDBエントリー: 1WAO 4JA9
• 分子名称: Serine/threonine-protein phosphatase 5, MAGNESIUM ION (3 entities in total)
• 機能のキーワード: pp5, activation, tau-dephosphorylation, neurodegenerative disease, ser/thr-protein phosphatase domain, tetratricopeptide repeat domain, hsp90, hydrolase
• 由来する生物種: Rattus norvegicus (brown rat,rat,rats)
• 細胞内の位置: Nucleus : P53042
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 55847.85

構造登録者

Haslbeck, V.,Helmuth, M.,Alte, F.,Popowicz, G.,Schmidt, W.,Weiwad, M.,Fischer, G.,Gemmecker, G.,Sattler, M.,Striggow, F.,Groll, M.,Richter, K. (登録日: 2013-02-18, 公開日: 2014-02-19, 最終更新日: 2023-09-20)

主引用文献

Haslbeck, V.,Drazic, A.,Eckl, J.M.,Alte, F.,Helmuth, M.,Popowicz, G.,Schmidt, W.,Braun, F.,Weiwad, M.,Fischer, G.,Gemmecker, G.,Sattler, M.,Striggow, F.,Groll, M.,Richter, K.
Selective activators of protein phosphatase 5 target the auto-inhibitory mechanism.
Biosci.Rep., 35:-, 2015

PubMed Abstract: 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 α-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.

PubMed: 26182372
DOI: 10.1042/BSR20150042

実験手法

X-RAY DIFFRACTION (2 Å)