3',5'-CYCLIC NUCLEOTIDE PHOSPHODIESTERASE FAMILIES 10 AND 4 AND THEIR COMPLEXES

3,5-环核苷酸磷酸二酯酶家族10和4及其复合物

• 批准号: 7602293
• 负责人: Hengming Ke
• 金额: $ 1.08万
• 依托单位: BROOKHAVEN SCIENCE ASSOC-BROOKHAVEN LAB
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7602293
• 关键词: Active Sites; Amino Acids; Attention; Bayer brand of vardenafil hydrochloride; Binding; Catalytic Domain; Chronic Obstructive Airway Disease; Chronic Obstructive Asthma; Cialis; Class; Complex; Computer Retrieval of Information on Scientific Projects Database; Cyclic AMP; Cyclic GMP; Cyclic Nucleotides; Data Set; Development; Enzymes; Erectile dysfunction; Family; Flavonoids; Funding; Genes; Grant; Human; Institution; Medical; Pharmaceutical Preparations; Phosphodiesterase Inhibitors; Protein Isoforms; Research; Research Personnel; Resources; Source; Structure; Substrate Specificity; Therapeutic; United States National Institutes of Health; Viagra; analog; base; human disease; inhibitor/antagonist; insight; male; mutant; novel; phosphoric diester hydrolase; sildenafil; tadalafil; vardenafil

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.

这个子项目是众多研究子项目之一