与AMP结合的磷酸二酯酶4（PDE4）的晶体结构揭示了磷酸二酯酶催化的一种机制。

The crystal structure of AMP-bound PDE4 suggests a mechanism for phosphodiesterase catalysis.

作者信息

Huai Qing, Colicelli John, Ke Hengming

机构信息

Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, North Carolina 27599-7260, USA.

出版信息

Biochemistry. 2003 Nov 18;42(45):13220-6. doi: 10.1021/bi034653e.

DOI:10.1021/bi034653e

PMID:14609333

Abstract

Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations of cyclic 3',5'-adenosine and guanosine monophosphates (cAMP and cGMP, respectively) by hydrolyzing them to AMP and GMP, respectively. Family-selective inhibitors of PDEs have been studied for treatment of various human diseases. However, the catalytic mechanism of cyclic nucleotide hydrolysis by PDEs has remained unclear. We determined the crystal structure of the human PDE4D2 catalytic domain in complex with AMP at 2.4 A resolution. In this structure, two divalent metal ions simultaneously interact with the phosphate group of AMP, implying a binuclear catalysis. In addition, the structure suggested that a hydroxide ion or a water bridging two metal ions may serve as the nucleophile for the hydrolysis of the cAMP phosphodiester bond.

摘要

环核苷酸磷酸二酯酶（PDEs）通过分别将3',5'-环腺苷酸和3',5'-环鸟苷酸（分别为cAMP和cGMP）水解为AMP和GMP来调节细胞内这两种环核苷酸的浓度。PDEs的家族选择性抑制剂已被研究用于治疗各种人类疾病。然而，PDEs催化环核苷酸水解的机制仍不清楚。我们以2.4埃的分辨率确定了与AMP结合的人PDE4D2催化结构域的晶体结构。在该结构中，两个二价金属离子同时与AMP的磷酸基团相互作用，这意味着存在双核催化。此外，该结构表明，连接两个金属离子的氢氧根离子或水分子可能作为水解cAMP磷酸二酯键的亲核试剂。