2H44

Crystal structure of PDE5A1 in complex with icarisid II

Summary for 2H44

• Entry DOI: 10.2210/pdb2h44/pdb
• Related: 2H40 2H42
• Descriptor: cGMP-specific 3',5'-cyclic phosphodiesterase, ZINC ION, MAGNESIUM ION, ... (5 entities in total)
• Functional Keywords: icarisid ii, flavonoid, pde5a inhibitor, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 38394.78

Authors

Wang, H.,Ke, H. (deposition date: 2006-05-23, release date: 2006-06-06, Last modification date: 2023-08-30)

Primary citation

Wang, H.,Liu, Y.,Huai, Q.,Cai, J.,Zoraghi, R.,Francis, S.H.,Corbin, J.D.,Robinson, H.,Xin, Z.,Lin, G.,Ke, H.
Multiple Conformations of Phosphodiesterase-5: Implications for enzyme function and drug development
J.Biol.Chem., 281:21469-21479, 2006

PubMed 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.

PubMed: 16735511
DOI: 10.1074/jbc.M512527200

Experimental method

X-RAY DIFFRACTION (1.8 Å)