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