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

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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.