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M504398200v1
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Papers In Press, published online ahead of print July 1, 2005
J. Biol. Chem, 10.1074/jbc.M504398200
Submitted on April 21, 2005
Revised on June 23, 2005
Accepted on July 1, 2005

Multiple elements jointly determine inhibitor selectivity of cyclic nucleotide phosphodiesterases 4 and 7

Huanchen Wang, Yudong Liu, Yuxiang Chen, Howard Robinson, and Hengming Ke

Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

Corresponding Author: hke{at}med.unc.edu

Phosphodiesterase (PDE) inhibitors have been widely studied as therapeutics for treatment of human diseases. However, the mechanism by which each PDE family recognizes selectively a category of inhibitors remains a puzzle. Here we report the crystal structure of PDE7A1 catalytic domain in complex with non-selective inhibitor 3-isobutyl-1-methylxanthine and kinetic analysis on the mutants of PDE7A1 and PDE4D2. Our studies suggest at least three elements playing critical roles in inhibitor selectivity: (1) the conformation and position of an invariant glutamine, (2) the natures of scaffolding residues, and (3) residues altering shape and size of the binding pocket. Kinetic analysis shows that single PDE7 to 4 mutations increase the sensitivity of PDE7 to PDE4 inhibitors, but are not sufficient to render the engineered enzymes comparable with the wild types. The triple S373Y/S377T/I412S mutation of PDE7A1 produces a PDE4-like enzyme, implying that multiple elements must work together to determine inhibitor selectivity.


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