Abstract
Crystal structures of seven phosphodiesterase families (PDE1-5, 7, 9) show a conserved core catalytic domain that contains about 300 amino acids and fourteen α-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 familyselective inhibitors. The kinetic analysis on the mutations of PDE7 to PDE4 suggests that the multiple elements must work together to define inhibitor selectivity.
Keywords: PDE4D5 splicing, Metal binding, cGMP, AMP Binding Residues, catalytic domains
Current Topics in Medicinal Chemistry
Title: Crystal Structures of Phosphodiesterases and Implications on Substrate Specificity and Inhibitor Selectivity
Volume: 7 Issue: 4
Author(s): Hengming Ke and Huanchen Wang
Affiliation:
Keywords: PDE4D5 splicing, Metal binding, cGMP, AMP Binding Residues, catalytic domains
Abstract: Crystal structures of seven phosphodiesterase families (PDE1-5, 7, 9) show a conserved core catalytic domain that contains about 300 amino acids and fourteen α-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 familyselective inhibitors. The kinetic analysis on the mutations of PDE7 to PDE4 suggests that the multiple elements must work together to define inhibitor selectivity.
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Cite this article as:
Ke Hengming and Wang Huanchen, Crystal Structures of Phosphodiesterases and Implications on Substrate Specificity and Inhibitor Selectivity, Current Topics in Medicinal Chemistry 2007; 7 (4) . https://dx.doi.org/10.2174/156802607779941242
DOI https://dx.doi.org/10.2174/156802607779941242 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
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