Implications of PDE4 structure on inhibitor selectivity across PDE families

International Journal of Impotence Research
Hengming Ke

Abstract

Phosphodiesterases (PDEs) control cellular concentrations of cyclic adenosine monophosphate (cAMP) or cyclic guanosine monophosphate (cGMP). PDE4 and PDE5 selectively hydrolyze cAMP and cGMP, respectively. PDE family members share approximately 25% sequence identity within a conserved catalytic domain of about 300 amino acids. Crystal structure analysis of PDE4's catalytic domain identifies two metal-binding sites: a high-affinity site and a low-affinity site, which probably bind zinc (Zn2+) and magnesium (Mg2+), respectively. Absolute conservation among the PDEs of two histidine and two aspartic acid residues for divalent metal binding suggests the importance of these amino acids in catalysis. Although active sites of PDEs are apparently structurally similar, PDE4 is specifically inhibited by selective inhibitors such as rolipram, while PDE5 is preferentially blocked by sildenafil. Modeling interactions of the PDE5 inhibitor sildenafil with the PDE4 active site may help explain inhibitor selectivity and provide useful information for the design of new inhibitors.

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Citations

Jun 21, 2012·Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology·Peng ZhongQing-Song Liu
Oct 21, 2005·Molecular Biology of the Cell·Yi-Hsien Su, Victor D Vacquier
Apr 6, 2016·Biomedicine & Pharmacotherapy = Biomédecine & Pharmacothérapie·Muhammad Zahid Khan
Aug 23, 2011·Neuropharmacology·Joshua S RodeferSamuel J Eckrich
Sep 27, 2005·Physiological Reviews·Susumu Seino, Tadao Shibasaki
Sep 25, 2019·Nutrients·Dorota Skrajnowska, Barbara Bobrowska-Korczak
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Aug 12, 2017·Journal of Medicinal Chemistry·Fredrik SvenssonDavid Bailey

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