Homo sapiens (human)
Phosphodiesterases (PDEs) are enzymes which hydrolyze the essential intercellular second messengers, cyclic AMP (cAMP) and cyclic GMP (cGMP). In functionally impaired cells, one often observes increased PDE activity and a decrease in the activity of enzymes which synthesize cAMP or cGMP. This leads to a cellular shortage of cAMP and cGMP. PDE inhibitors, thus, are essential for increasing the cellular levels of cAMP and cGMP. PDEs are well known targets for the treatment of the various diseases, including heart failure, depression, asthma, inflammation and erectile dysfunction. The inhibitors for some isozymes of 12 PDE gene families are popular as therapeutic agents for various diseases. PDE5, one of the PDE isozymes, is a cGMP-specific hydrolase. This isozyme is the target of the therapeutic product for erectile dysfunction, the PDE5 inhibitor Viagra, because the enzyme carries out the cGMP-hydrolyzing activity in human corpus cavernosum tissue.
The structure of the PDE5 catalytic domain containing the bound inhibitor (Viagra) has been determined. The ligand-binding pocket is approximately 10 angstrom deep, with a narrow opening and a wide inner space, which consists of four subsites: a metal-binding site, the core pocket, a hydrophobic pocket and a lid region. The inhibitor is designed to tightly interact with each of these sites via multiple hydrogen bonds and hydrophobic interactions. The four residues in the lid region form a "lid" over the pocket and narrow the entrance to the active site of PDE5.The amino acid sequences of the PDE5 ligand-binding pocket are favorable to specifically bind cGMP, when compared with the pocket of the cAMP-specific hydrolase PDE4. The authors of the structural study believe that this structure will further the development of selective PDE inhibitors.
Protein Data Bank (PDB)
author: Yuko Tsuchiya