Structural studies on substrate and inhibitor selectivity of phosphodiesterases

Cyclic nucleotide phosphodiesterases (PDEs) control the cellular concentration of "second messengers" adenosine or guanosine 3´, 5´-cyclic monophosphate (cAMP or cGMP). All PDEs contain a conserved catalytic domain, but each family possesses different substrate specificity and selective inhibitors. Selective inhibitors of PDEs have been studied as therapeutic agents for various diseases. However, many essential questions about the structure and function of PDEs remain mysteries. This dissertation will focus on inhibitor selectivity and substrate specificity studies of PDEs by X-ray crystallography, mutageneisis and enzymology. The crystal structure of PDE7 and kinetic analysis revealed multiple elements that jointly determinate inhibitor selectivity of PDEs. Crystal structures of PDE5 in complex with inhibitors showed multiple conformations of PDE5, providing insights into the enzyme function and for drug development. Crystal structures of PDE10 and structures of PDE4 subfamilies in complex with a PDE4D selective inhibitor will provide insights into the substrate specificity and subfamily inhibitor selectivity