Zhang Kam Y J, Card Graeme L, Suzuki Yoshihisa, Artis D Richard, Fong Daniel, Gillette Sam, Hsieh Davin, Neiman Joshua, West Brian L, Zhang Chao, Milburn Michael V, Kim Sung-Hou, Schlessinger Joseph, Bollag Gideon
Plexxikon Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA.
Mol Cell. 2004 Jul 23;15(2):279-86. doi: 10.1016/j.molcel.2004.07.005.
Phosphodiesterases (PDEs) comprise a family of enzymes that modulate the immune response, inflammation, and memory, among many other functions. There are three types of PDEs: cAMP-specific, cGMP-specific, and dual-specific. Here we describe the mechanism of nucleotide selectivity on the basis of high-resolution co-crystal structures of the cAMP-specific PDE4B and PDE4D with AMP, the cGMP-specific PDE5A with GMP, and the apo-structure of the dual-specific PDE1B. These structures show that an invariant glutamine functions as the key specificity determinant by a "glutamine switch" mechanism for recognizing the purine moiety in cAMP or cGMP. The surrounding residues anchor the glutamine residue in different orientations for cAMP and for cGMP. The PDE1B structure shows that in dual-specific PDEs a key histidine residue may enable the invariant glutamine to toggle between cAMP and cGMP. The structural understanding of nucleotide binding enables the design of new PDE inhibitors that may treat diseases in which cyclic nucleotides play a critical role.
磷酸二酯酶（PDEs）是一类酶，可调节免疫反应、炎症和记忆等多种功能。磷酸二酯酶有三种类型：特异性作用于环磷酸腺苷（cAMP）的、特异性作用于环磷酸鸟苷（cGMP）的以及具有双重特异性的。在此，我们基于特异性作用于cAMP的磷酸二酯酶4B（PDE4B）和磷酸二酯酶4D（PDE4D）与腺苷一磷酸（AMP）的高分辨率共晶体结构、特异性作用于cGMP的磷酸二酯酶5A（PDE5A）与鸟苷一磷酸（GMP）的高分辨率共晶体结构以及具有双重特异性的磷酸二酯酶1B（PDE1B）的无配体结构，描述核苷酸选择性的机制。这些结构表明，一个不变的谷氨酰胺通过“谷氨酰胺开关”机制作为关键的特异性决定因素，用于识别cAMP或cGMP中的嘌呤部分。周围的残基将谷氨酰胺残基以不同方向固定，分别对应cAMP和cGMP。PDE1B的结构表明，在具有双重特异性的磷酸二酯酶中，一个关键的组氨酸残基可能使不变的谷氨酰胺在cAMP和cGMP之间切换。对核苷酸结合的结构理解有助于设计新的磷酸二酯酶抑制剂，用于治疗环核苷酸起关键作用的疾病。
