A Reduced-Amide Inhibitor of Pin1 Binds in a Conformation Resembling a Twisted-Amide Transition State

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• 作者：Guoyan G. Xu ; Yan Zhang ; Ana Y. Mercedes-Camacho ; Felicia A. Etzkorn
• 刊名：Biochemistry
• 出版年：2011
• 出版时间：November 8, 2011
• 年：2011
• 卷：50
• 期：44
• 页码：9545-9550
• 全文大小：310K
• 年卷期：v.50,no.44(November 8, 2011)
• ISSN：1520-4995

文摘

The mechanism of the cell cycle regulatory peptidyl prolyl isomerase (PPIase), Pin1, was investigated using reduced-amide inhibitors designed to mimic the twisted-amide transition state. Inhibitors, R-pSer-唯[CH₂N]-Pro-2-(indol-3-yl)ethylamine, 1 [R = fluorenylmethoxycarbonyl (Fmoc)] and 2 (R = Ac), of Pin1 were synthesized and bioassayed. Inhibitor 1 had an IC₅₀ value of 6.3 渭M, which is 4.5-fold better for Pin1 than our comparable ground-state analogue, a cis-amide alkene isostere-containing inhibitor. The change of Fmoc to Ac in 2 improved aqueous solubility for structural determination and resulted in an IC₅₀ value of 12 渭M. The X-ray structure of the complex of 2 bound to Pin1 was determined to 1.76 脜 resolution. The structure revealed that the reduced amide adopted a conformation similar to the proposed twisted-amide transition state of Pin1, with a trans-pyrrolidine conformation of the prolyl ring. A similar conformation of substrate would be destabilized relative to the planar amide conformation. Three additional reduced amides, with Thr replacing Ser and l- or d-pipecolate (Pip) replacing Pro, were slightly weaker inhibitors of Pin1.