The Crystal Structure of AMP-Bound PDE4 Suggests a Mechanism for Phosphodiesterase Catalysis

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• 作者：Qing Huai ; John Colicelli ; and Hengming Ke
• 刊名：Biochemistry
• 出版年：2003
• 出版时间：November 18, 2003
• 年：2003
• 卷：42
• 期：45
• 页码：13220 - 13226
• 全文大小：453K
• 年卷期：v.42,no.45(November 18, 2003)
• ISSN：1520-4995

文摘

Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations of cyclic3',5'-adenosine and guanosine monophosphates (cAMP and cGMP, respectively) by hydrolyzing them toAMP and GMP, respectively. Family-selective inhibitors of PDEs have been studied for treatment ofvarious human diseases. However, the catalytic mechanism of cyclic nucleotide hydrolysis by PDEs hasremained unclear. We determined the crystal structure of the human PDE4D2 catalytic domain in complexwith AMP at 2.4 Å resolution. In this structure, two divalent metal ions simultaneously interact with thephosphate group of AMP, implying a binuclear catalysis. In addition, the structure suggested that ahydroxide ion or a water bridging two metal ions may serve as the nucleophile for the hydrolysis of thecAMP phosphodiester bond.