Structural basis for the activity of drugs that inhibit phosphodiesterases

Structure. 2004 Dec;12(12):2233-47. doi: 10.1016/j.str.2004.10.004.


Phosphodiesterases (PDEs) comprise a large family of enzymes that catalyze the hydrolysis of cAMP or cGMP and are implicated in various diseases. We describe the high-resolution crystal structures of the catalytic domains of PDE4B, PDE4D, and PDE5A with ten different inhibitors, including the drug candidates cilomilast and roflumilast, for respiratory diseases. These cocrystal structures reveal a common scheme of inhibitor binding to the PDEs: (i) a hydrophobic clamp formed by highly conserved hydrophobic residues that sandwich the inhibitor in the active site; (ii) hydrogen bonding to an invariant glutamine that controls the orientation of inhibitor binding. A scaffold can be readily identified for any given inhibitor based on the formation of these two types of conserved interactions. These structural insights will enable the design of isoform-selective inhibitors with improved binding affinity and should facilitate the discovery of more potent and selective PDE inhibitors for the treatment of a variety of diseases.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Binding Sites
  • Crystallography, X-Ray
  • Phosphodiesterase Inhibitors / chemistry*
  • Phosphoric Diester Hydrolases / metabolism*
  • Protein Structure, Tertiary


  • Phosphodiesterase Inhibitors
  • Phosphoric Diester Hydrolases

Associated data

  • PDB/1XLX
  • PDB/1XLZ
  • PDB/1XM4
  • PDB/1XM6
  • PDB/1XMU
  • PDB/1XMY
  • PDB/1XN0
  • PDB/1XOM
  • PDB/1XON
  • PDB/1XOQ
  • PDB/1XOR
  • PDB/1XOT
  • PDB/1XOX
  • PDB/1XOZ
  • PDB/1XP0