Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development.

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Wang H, Liu Y, Huai Q, Cai J, Zoraghi R, Francis SH, Corbin JD, Robinson H, Xin Z, Lin G, Ke H

Multiple conformations of phosphodiesterase-5: implications for enzyme function and drug development.

J Biol Chem. 2006 Jul 28;281(30):21469-79. Epub 2006 May 30.

PubMed ID

16735511 [ View in PubMed

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Abstract

Phosphodiesterase-5 (PDE5) is the target for sildenafil, vardenafil, and tadalafil, which are drugs for treatment of erectile dysfunction and pulmonary hypertension. We report here the crystal structures of a fully active catalytic domain of unliganded PDE5A1 and its complexes with sildenafil or icarisid II. These structures together with the PDE5A1-isobutyl-1-methylxanthine complex show that the H-loop (residues 660-683) at the active site of PDE5A1 has four different conformations and migrates 7-35A upon inhibitor binding. In addition, the conformation of sildenafil reported herein differs significantly from those in the previous structures of chimerically hybridized or almost inactive PDE5. Mutagenesis and kinetic analyses confirm that the H-loop is particularly important for substrate recognition and that invariant Gly(659), which immediately precedes the H-loop, is critical for optimal substrate affinity and catalytic activity.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Sildenafil	cGMP-specific 3',5'-cyclic phosphodiesterase	Protein	Humans	Yes	Inhibitor	Details