title: Structural basis for the activity of drugs that inhibit phosphodiesterases.
abstract: 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.
authors.affiliation: Plexxikon, Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA.
authors.forename: Graeme L
authors.initials: GL
authors.lastname: Card
authors.forename: Bruce P
authors.initials: BP
authors.lastname: England
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Daniel
authors.initials: D
authors.lastname: Fong
authors.forename: Ben
authors.initials: B
authors.lastname: Powell
authors.forename: Byunghun
authors.initials: B
authors.lastname: Lee
authors.forename: Catherine
authors.initials: C
authors.lastname: Luu
authors.forename: Maryam
authors.initials: M
authors.lastname: Tabrizizad
authors.forename: Sam
authors.initials: S
authors.lastname: Gillette
authors.forename: Prabha N
authors.initials: PN
authors.lastname: Ibrahim
authors.forename: Dean R
authors.initials: DR
authors.lastname: Artis
authors.forename: Gideon
authors.initials: G
authors.lastname: Bollag
authors.forename: Michael V
authors.initials: MV
authors.lastname: Milburn
authors.forename: Sung-Hou
authors.initials: SH
authors.lastname: Kim
authors.forename: Joseph
authors.initials: J
authors.lastname: Schlessinger
authors.forename: Kam Y J
authors.initials: KY
authors.lastname: Zhang
mesh_terms: D001665:Binding Sites; D018360:Crystallography, X-Ray; D010726:Phosphodiesterase Inhibitors / Q000737:chemistry*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D017434:Protein Structure, Tertiary
chemical_list: D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases