PT  - JOURNAL ARTICLE
AU  - Huanchen Wang
AU  - Mengchun Ye
AU  - Howard Robinson
AU  - Sharron H. Francis
AU  - Hengming Ke
TI  - Conformational Variations of Both Phosphodiesterase-5 and Inhibitors Provide the Structural Basis for the Physiological Effects of Vardenafil and Sildenafil
AID  - 10.1124/mol.107.040212
DP  - 2008 Jan 01
TA  - Molecular Pharmacology
PG  - 104--110
VI  - 73
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/73/1/104.short
4100  - http://molpharm.aspetjournals.org/content/73/1/104.full
SO  - Mol Pharmacol2008 Jan 01; 73
AB  - Vardenafil has higher affinity to phosphodiesterase-5 (PDE5) than sildenafil and lower administered dosage for the treatment of erectile dysfunction. However, the molecular basis for these differences is puzzling because two drugs have similar chemical structures. Reported here is a crystal structure of the fully active and nonmutated PDE5A1 catalytic domain in complex with vardenafil. The structure shows that the conformation of the H-loop in the PDE5A1-vardenafil complex is different from those of any known structures of the unliganded PDE5 and its complexes with the inhibitors. In addition, the molecular configuration of vardenafil differs from that of sildenafil when bound to PDE5. It is noteworthy that the binding of vardenafil causes loss of the divalent metal ions that have been observed in all the previously published PDE structures. The conformational variation of both PDE5 and the inhibitors provides structural insight into the different potencies of the drugs. The American Society for Pharmacology and Experimental Therapeutics