CRYSTAL STRUCTURE OF MAMMALIAN ADENYLYL CYCLASE IN COMPLEX WITH 2',3'-SUBSTITUTE

这个子项目是许多研究子项目中的一个 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 研究中心，而研究中心不一定是研究者所在的机构。 膜腺苷酸环化酶（mACs）通过将ATP转化为环AMP在信号转导中起重要作用，因此是重要的潜在药物靶点。我们的小组已经解决了与活化G蛋白α亚基复合的mAC的晶体结构。 与我们在里根斯堡的合作者一起，我们发现了一类新的2 '，3'-取代的嘌呤和嘧啶核苷酸抑制剂。在这个家庭中的30多个化合物的系统动力学分析，已经确定了几个高度有效的抑制剂与Ki值在亚纳摩尔范围。 与该家族中的三个配体结合的mAC的晶体结构揭示了与典型ATP类似物不同的新的结合机制。我们已经开发了一个药效团模型来设计一个原型抑制剂，与酶内的不同亚位点相互作用。 我们计划确定结合到这些设计的抑制剂中的两个的mAC的结构。 一系列基于毛喉素的化合物也将进行测试。

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. Membrane adenylyl cyclases (mACs) play an essential role in signal transduction by converting ATP to cyclic AMP and are therefore important potential drug targets. The crystal structure of mAC in complex with the activating G protein alpha subunit has been solved by our group. With our collaborators in Regensburg, we have discovered a new class of 2',3'- substituted purine and pyrimidine nucleotide inhibitors. Systematic kinetic analysis of over 30 compounds in this family, have identified several highly potent inhibitors with Ki values in the sub-nanomolar ranges. Crystal structures of mAC bound to three ligands in this family have revealed a novel mechanism of binding that is distinct from that of typical ATP analogs. We have developed a pharmacophore model to design a prototype inhibitors that interact with distinct subsites within the enzyme. We plan to determine the structures of mAC bound to two of these designed inhibitors. A series of compounds based on forskolin will also be tested.