ABSTRACT

Cyclic nucleotide phosphodiesterases (PDEs) hydrolyze the second messengers cyclic adenosine monophosphate (cAMP) and cyclic guanine monophosphate (cGMP) to AMP and GMP. This chapter describes the current knowledge on the three-dimensional structures of the catalytic domains of the PDE families and discuss structural hints on hydrolysis mechanism, substrate specificity, and inhibitor selectivity. The PDE molecules can be divided into three regions: an N-terminal splicing region, a regulatory domain, and a C-terminal catalytic domain. Extensive structural studies have revealed detailed interactions of inhibitors at the active site of PDEs and led to identification of subpockets or elements that are important for the recognition of nonselective and family-selective inhibitors. Inhibitor selectivity is an essential issue for the improvement of drug efficacy and minimization of side effects. Structure-based development of novel selective inhibitors and an analysis of quantitative structure–activity relationship will confirm and extend our understanding of inhibitor selectivity.