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

2,3-取代基哺乳动物腺苷酸环化酶的晶体结构

• 批准号: 7954485
• 负责人: TUNG-CHUNG MOU
• 金额: $ 0.1万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-03-01 至 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7954485
• 关键词: Adenylate Cyclase; Binding; Classification; Complex; Computer Retrieval of Information on Scientific Projects Database; Cyclic AMP; Drug Delivery Systems; Enzymes; Family; Forskolin; Funding; GTP-Binding Protein alpha Subunits; Grant; Institution; Kinetics; Ligands; Membrane; Modeling; Play; Purines; Pyrimidine Nucleotides; Research; Research Personnel; Resources; Role; Series; Signal Transduction; Source; Structure; Testing; United States National Institutes of Health; analog; base; compound 30; design; inhibitor/antagonist; novel; pharmacophore; prototype; purine; structural biology; synchrotron radiation

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.

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。 膜腺苷酰环化酶(MACs)通过将ATP转化为环状AMP在信号转导中发挥重要作用，因此是重要的潜在药物靶点。本课题组已经解决了Mac与激活G蛋白α亚基形成的复合体的晶体结构问题。与我们在雷根斯堡的合作者一起，我们发现了一类新的2‘，3’-取代嘌呤和嘧啶核苷酸抑制剂。对这一家族中的30多个化合物进行了系统的动力学分析，发现了几个KI值在亚纳摩尔范围内的高效缓蚀剂。与该家族中的三个配体结合的Mac的晶体结构揭示了一种与典型的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，它与酶中不同的亚基相互作用。我们计划确定Mac与其中两种设计的抑制剂结合的结构。一系列基于Forskolin的化合物也将进行测试。