Conformation-Directed Catalysis and Coupled Enzyme鈥揝ubstrate Dynamics in Pin1 Phosphorylation-Dependent Cis鈥揟rans Isomerase

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• 作者：Hector A. Velazquez ; Donald Hamelberg
• 刊名：Journal of Physical Chemistry B
• 出版年：2013
• 出版时间：October 3, 2013
• 年：2013
• 卷：117
• 期：39
• 页码：11509-11517
• 全文大小：498K
• 年卷期：v.117,no.39(October 3, 2013)
• ISSN：1520-5207

文摘

Human peptidyl鈥損rolyl cis鈥搕rans isomerase NIMA-interacting 1 (Pin1) is an essential enzyme in numerous phosphorylation-dependent regulatory pathways and has been implicated in many diseases, including cancer and Alzheimers. Pin1 specifically catalyzes cis鈥搕rans isomerization of prolyl鈥損eptide bonds preceded by phosphorylated serine or phosphorylated threonine in its protein substrates. Yet, little is known about the catalytic mechanism of Pin1 in atomistic detail. Here, we present results from accelerated molecular dynamics simulations to show that catalysis occurs along a restricted path of the backbone configuration of the substrate, selecting out specific conformations of the substrate in the active site of Pin1. We show that the dynamics of Pin1 and the enzyme鈥搒ubstrate interactions are intricately coupled to isomerization during catalysis. The strength of the interactions between the phosphate binding pocket of Pin1 and the phosphate moiety of the substrate is dictated by the state of the substrate during catalysis. We also show that the transition-state configuration of the substrate binds better than the cis and trans states to the catalytic domain of Pin1, suggesting that Pin1 catalyzes its substrate by noncovalently stabilizing the transition state. These results suggest an atomistic detail understanding of the catalytic mechanism of Pin1 that is necessary for the design of novel inhibitors and the treatment of several diseases.