Structural basis for the activity of drugs that inhibit phosphodiesterases |
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Authors: | Card Graeme L England Bruce P Suzuki Yoshihisa Fong Daniel Powell Ben Lee Byunghun Luu Catherine Tabrizizad Maryam Gillette Sam Ibrahim Prabha N Artis Dean R Bollag Gideon Milburn Michael V Kim Sung-Hou Schlessinger Joseph Zhang Kam Y J |
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Affiliation: | Plexxikon, Inc., 91 Bolivar Drive, Berkeley, CA 94710, USA. |
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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. |
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