Viagra Research Today is a free monthly online journal that collates and summarizes the latest research about Viagra, including details on sildenafil, erectile dysfunction, impotence, side-effects, alternatives.

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

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

Department of Biochemistry and Biophysics, University of North Carolina, Chapel Hill, 27599-7260, USA.

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.

Published 24 July 2006 in J Biol Chem, 281(30): 21469-79.
Full-text of this article is available online (may require subscription).

© 2004-2008 Viagra Research Today. All Rights Reserved.