Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity.
Crystal structures of seven phosphodiesterase families (PDE1-5, 7, 9) show a conserved core catalytic domain that contains about 300 amino acids and fourteen alpha-helices. The catalytic domains of the PDE families 1-4, 7, and 9 have a uniform conformation. However, the H-loop at the active site of PDE5 shows four different conformations upon binding of inhibitors, probably implying a special mechanism for recognition of substrates and inhibitors by PDE5. The active site of all PDE families contains two divalent metal ions: zinc and probably magnesium. The PDE4-AMP and PDE5-GMP structures reveal the conserved interactions of the phosphate groups of the products AMP and GMP, and thus suggest a universal mechanism of nucleophilic attack for all PDE families. The substrate specificity has not been well understood. This review will comment on the early proposal, "glutamine switch", on basis of the recent biochemical and structural information. The PDE-inhibitor structures have identified a common subpocket for non-selective binding of all inhibitors and potential elements for recognition of family-selective inhibitors. The kinetic analysis on the mutations of PDE7 to PDE4 suggests that the multiple elements must work together to define inhibitor selectivity.
Ke
Hengming
H
Department of Biochemistry and Biophysics and Lineberger Comprehensive Cancer Center, The University of North Carolina, Chapel Hill, NC 27599-7260, USA. hke@med.unc.edu
Wang
Huanchen
H
D000595:Amino Acid Sequence; D020134:Catalytic Domain; D008670:Metals / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010726:Phosphodiesterase Inhibitors / Q000378:metabolism / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry* / Q000378:metabolism; D011487:Protein Conformation; D013379:Substrate Specificity
D008670:Metals; D010726:Phosphodiesterase Inhibitors; D010727:Phosphoric Diester Hydrolases