Discovery and Characterization of a Nonphosphorylated Cyclic Peptide Inhibitor of the Peptidylprolyl Isomerase, Pin1

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• 作者：Kelly E. Duncan ; Brian R. Dempsey ; Lauren E. Killip ; Jarrett Adams ; Melanie L. Bailey ; Gilles A. Lajoie ; David W. Litchfield ; Christopher J. Brandl ; Gary S. Shaw ; Brian H. Shilton
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：June 9, 2011
• 年：2011
• 卷：54
• 期：11
• 页码：3854-3865
• 全文大小：1151K
• 年卷期：v.54,no.11(June 9, 2011)
• ISSN：1520-4804

文摘

Phage panning led to the discovery of a disulfide-cyclized peptide CRYPEVEIC that inhibits Pin1 activity with a K_I of 0.5 渭M. NMR chemical shift perturbation experiments show that cyclic CRYPEVEIC binds to the active site of Pin1. Pin1 residues K63 and R68, which bind the phosphate of substrate peptides, do not show a significant chemical shift change in response to binding of cyclic CRYPEVEIC, consistent with absence of phosphate on the peptide. Cyclic CRYPEVEIC adopts a stable conformation with the side chains of the Y, P, V, and I residues packed together on one side of the ring. Cyclic CRYPEVEIC in solution exists as a mixture of two species, with a 1:4 cis/trans ratio for the Y鈥揚 bond. This mixture is stabilized to a single conformation when bound to Pin1. The constrained structure of cyclic CRYPEVEIC apparently facilitates high affinity binding without the presence of a phosphate group.