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Cyclohexyl Ketone Inhibitors of Pin1 Dock in a Trans- Diaxial Cyclohexane Conformation.
- Source :
-
PLoS ONE . Sep2012, Vol. 7 Issue 9, Special section p1-8. 8p. - Publication Year :
- 2012
-
Abstract
- Cyclohexyl ketone substrate analogue inhibitors (Ac--pSer-ψ[C = OCH]-Pip--tryptamine) of Pin1, the cell cycle regulatory peptidyl-prolyl isomerase (PPlase), were designed and synthesized as potential electrophilic acceptors for the Pin1 active site Cys113 nucleophile to test a proposed nucleophilic addition-isomerization mechanism. Because they were weak inhibitors, models of all three stereoisomers were docked into the active site of Pin1. Each isomer consistently minimized to a trans-diaxial cyclohexane conformation. From this, we hypothesize that Pin1 stretches substrates into a trans-pyrrolidine conformation to lower the barrier to isomerization. Our reduced amide inhibitor of Pin1 adopted a similar trans-pyrrolidine conformation in the crystal structure. The molecular model of 1, which mimics the L-Ser-L-Pro stereochemistry, in the Pin1 active site showed a distance of 4.4 Å, and an angle of 31° between Cys113-S and the ketone carbon. The computational models suggest that the mechanism of Pin1 PPIase is not likely to proceed through nucleophilic addition. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 7
- Issue :
- 9
- Database :
- Academic Search Index
- Journal :
- PLoS ONE
- Publication Type :
- Academic Journal
- Accession number :
- 82446225
- Full Text :
- https://doi.org/10.1371/journal.pone.0044226