Atomic structure of PDE4: Insights into phosphodiesterase mechanism and specificity

Cyclic nucleotides are second messengers that are essential in vision, musc le contraction, neurotransmission, exocytosis, cell growth, and differentia tion. These molecules are degraded by a family of enzymes known as phosphod iesterases, which serve a critical function by regulating the intracellular concentration of cyclic nucleotides. We have determined the three-dimensio nal structure of the catalytic domain of phosphodiesterase 4B2B to 1.77 ang strom resolution. The active site has been identified and contains a cluste r of two metal atoms. The structure suggests the mechanism of action and ba sis for specificity and will provide a framework for structure-assisted dru g design for members of the phosphodiesterase family.