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

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 中心，但不一定是研究者所在的机构。 环核苷酸磷酸二酯酶（PDE）是控制第二信使cAMP和cGMP的细胞浓度的酶。21个人类PDE基因编码超过80种亚型，可归类为elevent家族。所有PDE都含有一个约300个氨基酸的保守催化结构域，但每个PDE家族都有其特定的底物和选择性抑制剂。PDE的家族选择性抑制剂已被广泛研究作为治疗各种人类疾病的治疗剂。例如，PDE 5抑制剂西地那非（伟哥）、伐地那非（艾力达）和他达拉非（希爱力）是用于治疗男性勃起功能障碍的药物，并且已经研究了PDE 4抑制剂用于治疗哮喘和慢性阻塞性肺病。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，PDE家族的保守催化结构域如何选择性地识别其优选的底物和抑制剂仍然是未知的。该项目的目标是收集大约10个关于PDE 10与底物类似物复合物和PDE 4与选择性抑制剂复合物的数据集。与cAMP或cGMP复合的无活性PDE 10突变体将显示这两种底物如何共同和不同地结合活性位点，从而了解底物特异性。与亚家族选择性抑制剂和类黄酮复合的PDE 4结构不仅说明了PDE 4亚家族的选择性，而且还为开发一类新的PDE 4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.