ABSTRACT
Phosphodiesterases (PDEs) are enzymes that control the level of cyclic adenosine monophosphate and cyclic guanosine monophosphate, two ubiquitous second messengers that mediate biological responses to a variety of extracellular cues including hormones, neurotransmitters, chemokines, and cytokines. PDEs achieve their nucleotide selectivity through a glutamine switch mechanism. The cocrystal structures of many inhibitors in complex with various PDEs have revealed a hydrophobic clamp that anchors these inhibitors in the active site. The cocrystal structure of phosphodiesterase 3B in complex with a dihydropyridazine inhibitor showed that the inhibitor is bound in an extended conformation with the central aromatic ring overlapping with the purine ring of cyclic nucleotides. Structural information offers potential in formulating the rational design of more potent and selective phosphodiesterase 4 inhibitors. Advances in the structural biology of PDE catalytic domains have revealed the mechanism of cyclic nucleotide selectivity and structural basis of inhibitor binding.
