1. Cyclohexyl Ketone Inhibitors of Pin1 Dock in a Trans- Diaxial Cyclohexane Conformation.
- Author
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Xu, Guoyan G., Slebodnick, Carla, Etzkorn, Felicia A., and Barchi, Joseph J.
- Subjects
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CYCLOHEXANONES , *CELL cycle , *NUCLEOPHILIC addition (Chemistry) , *STEREOISOMERS , *ISOMERASES - 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]
- Published
- 2012
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