PROSITE documentation PDOC001163'5'-cyclic nucleotide phosphodiesterase domain signature and profile
3'5'-cyclic nucleotide phosphodiesterases (EC 3.1.4.17) (PDEases) comprise a family of enzymes that modulate the immune response, inflammation, and memory, among many other functions. They catalyze the hydrolysis of cyclic nucleotides, cAMP and cGMP, to the corresponding nucleoside 5' monophosphates [1,2]. There are at least seven different subfamilies of PDEases [3,E1]:
- Type 1, calmodulin/calcium-dependent PDEases.
- Type 2, cGMP-stimulated PDEases.
- Type 3, cGMP-inhibited PDEases.
- Type 4, cAMP-specific PDEases.
- Type 5, cGMP-specific PDEases.
- Type 6, rhodopsin-sensitive cGMP-specific PDEases.
- Type 7, High affinity cAMP-specific PDEases.
All of these forms contain a catalytic domain of approximately 270 amino acids at the carboxyl terminus. Regulatory domains that vary widely among the PDEase subfamilies flank the catalytic core and include regions that autoinhibit the catalytic domains as well as targeting sequences that control subcellular localization [2].
The PDEase catalytic domains adopt a compact α-helical structure consisting of 16 α-helices that can be divided into three subdomains (see <PDB:1F0J>). The active site of PDEases is a deep pocket formed by the tree subdomains and can be divided into two major subpockets for binding of divalent metals and substrate/inhibitors, respectively. The active site of all PDEase domains contains two divalent metal ions: zinc and probably magnesium [2,4,5].
We have derived a signature pattern from a stretch of 12 residues that contains two conserved histidines. We also developed a profile that covers the whole PDEase catalytic domain.
Note:Slime mold extracellular PDEase and yeast low-affinity PDEase (gene PDE1) do not show any similarity with the above enzymes and belong to another class of PDEases (see <PDOC00530>).
Last update:October 2017 / Text revised; profile added.
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PROSITE methods (with tools and information) covered by this documentation:
| 1 | Authors | Charbonneau H. Beier N. Walsh K.A. Beavo J.A. |
| Title | Identification of a conserved domain among cyclic nucleotide phosphodiesterases from diverse species. | |
| Source | Proc. Natl. Acad. Sci. U.S.A. 83:9308-9312(1986). | |
| PubMed ID | 3025833 |
| 2 | Authors | Zhang K.Y.J. Card G.L. Suzuki Y. Artis D.R. Fong D. Gillette S. Hsieh D. Neiman J. West B.L. Zhang C. Milburn M.V. Kim S.-H. Schlessinger J. Bollag G. |
| Title | A glutamine switch mechanism for nucleotide selectivity by phosphodiesterases. | |
| Source | Mol. Cell 15:279-286(2004). | |
| PubMed ID | 15260978 | |
| DOI | 10.1016/j.molcel.2004.07.005 |
| 3 | Authors | Beavo J.A. Reifsnyder D.H. |
| Title | Primary sequence of cyclic nucleotide phosphodiesterase isozymes and the design of selective inhibitors. | |
| Source | Trends Pharmacol. Sci. 11:150-155(1990). | |
| PubMed ID | 2159198 |
| 4 | Authors | Xu R.X. Hassell A.M. Vanderwall D. Lambert M.H. Holmes W.D. Luther M.A. Rocque W.J. Milburn M.V. Zhao Y. Ke H. Nolte R.T. |
| Title | Atomic structure of PDE4: insights into phosphodiesterase mechanism and specificity. | |
| Source | Science 288:1822-1825(2000). | |
| PubMed ID | 10846163 |
| 5 | Authors | Ke H. Wang H. |
| Title | Crystal structures of phosphodiesterases and implications on substrate specificity and inhibitor selectivity. | |
| Source | Curr. Top. Med. Chem. 7:391-403(2007). | |
| PubMed ID | 17305581 |
| E1 | Source | http://depts.washington.edu/pde/ |
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