3',5'-CYCLIC NUCLEOTIDE PHOSPHODIESTERASE FAMILIES AND THEIR COMPLEXES WITH INHI

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 环核苷酸磷酸二酯酶(PDE)是控制细胞内第二信使cAMP和cGMP浓度的酶。21个人类PDE基因编码80多种异构体，可归类为ELEVE家族。所有的PDE都含有一个保守的催化结构域，大约有300个氨基酸，但每个PDE家族都有其特定的底物和选择性的抑制剂。家族选择性的PDEs抑制剂已被广泛研究为治疗各种人类疾病的药物。例如，PDE5抑制剂西地那非(伟哥)、伐地那非(Levitra)和他达拉非(Cialis)是治疗男性勃起功能障碍的药物，PDE4抑制剂已被研究用于治疗哮喘和慢性阻塞性肺疾病。由于PDE在医学上的广泛应用，它受到了学术界和工业界的广泛关注。然而，目前尚不清楚PDE家族的保守催化结构域如何选择性地识别它们的首选底物和抑制剂。这个项目的目标是收集关于PDE10与底物类似物的复合体和关于PDE4与选择性抑制剂的复合体的大约10个数据集。无活性的PDE10突变体与cAMP或cGMP的复合体将显示这两种底物如何共同和不同地结合到活性部位，从而深入了解底物的特异性。PDE4与亚家族选择性抑制剂和类黄酮类化合物形成的络合物不仅说明了PDE4亚家族的选择性，而且为开发新型的PDE4抑制剂提供了基础。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Cyclic nucleotide phosphodiesterases (PDEs) are enzymes controlling cellular concentration of second messangers cAMP and cGMP. Twenty one human genes of PDE encode over eighty isoforms that can be categorized into elevent families. All PDEs contain a conserved catalytic domain with about 300 amino acids, but each PDE family possesses its specific substrates and selective inhibitors. Family-selective inhibitors of PDEs have been widely studied as therapeutics for treatment of various human diseases. For example, the PDE5 inhibitors sildenafil (Viagra), vardenafil (Levitra), and tadalafil (Cialis) are drugs for treatment of male erectile dysfunction and PDE4 inhibitors have been studied for treatment of asthma and chronic obstructive pulmonary disease. For the wide medical applications, PDE has received intensive attention from both academic and industrial groups. However, it remains unknown how the conserved catalytic domains of the PDE families selectively recognize their preferred substrates and inhibitors. This project targets to collect about ten data sets on PDE10 in complex with substrate analogs and on PDE4 in complex with selective inhibitors. The inactive PDE10 mutant in complex with cAMP or cGMP will show how these two substrates bind commonly and differently to the active site, thus an insight into substrate specificity. The PDE4 structures in complex with a subfamily-selective inhibitor and with flavonoids will not only illustrate the PDE4 subfamily selectivity, but also provide a basis for development of a novel class of PDE4 inhibitors.