The crystal structure of AMP-bound PDE4 suggests a mechanism for phosphodiesterase catalysis
The crystal structure of AMP-bound PDE4 suggests a mechanism for phosphodiesterase catalysis
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DOI：
10.1021/bi034653e
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发表时间：
2003-11-18
期刊：
影响因子：
2.9
通讯作者：
Ke, HM
中科院分区：
文献类型：
--
作者：
Huai, Q;Colicelli, J;Ke, HM
环核苷酸磷酸二酯酶（PDEs）通过将环3′，5′-腺苷和鸟苷单磷酸（cAMP和cGMP）分别水解为AMP和GMP来调节细胞内的浓度。家族选择性PDEs抑制剂已被研究用于治疗各种人类疾病。然而，PDEs水解环核苷酸的催化机制尚不清楚。我们以2.4埃的分辨率测定了人PDE4D2催化结构域在AMP配合物中的晶体结构。在这种结构中，两个二价金属离子同时与AMP的磷酸基相互作用，意味着双核催化。此外，该结构表明氢氧化物离子或桥接两个金属离子的水可能是cAMP磷酸二酯键水解的亲核试剂。
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 Angstrom 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.