ArticleBiochemistry2008
Kinetic and structural studies of phosphodiesterase-8A and implication on the inhibitor selectivity.
Article in Biochemistry, 2008. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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Who cites it
37 citing papers in PubMed, 79 citations in OpenAlex.
- Phosphodiesterase 8 regulation of excitation-contraction coupling as a target for cardiovascular disease: is it my turn now?American journal of physiology. Heart and circulatory physiology · 2026Review
- Conformational Dynamics and Allostery in the cAMP-Protein Kinase A Signalosome.Advances in experimental medicine and biology · 2026Review
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Abnormal phosphorylation / dephosphorylation and CaHeart failure reviews · 2024Review
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- Impaired cAMP processivity by phosphodiesterase-protein kinase A complexes in acrodysostosis.Frontiers in molecular biosciences · 2023Article
- Structure-based discovery of orally efficient inhibitorsActa pharmaceutica Sinica. B · 2022Article
- Treatment of Experimental Autoimmune Encephalomyelitis with an Inhibitor of Phosphodiesterase-8 (PDE8).Cells · 2022Article
- Characterization of the cAMP phosphodiesterase domain in plant adenylyl cyclase/cAMP phosphodiesterase CAPE from the liverwort Marchantia polymorpha.Journal of plant research · 2022Article
- Development of Phosphodiesterase-Protein-Kinase Complexes as Novel Targets for Discovery of Inhibitors with Enhanced Specificity.International journal of molecular sciences · 2021Article
- The Role of PDE8 in T Cell Recruitment and Function in Inflammation.Frontiers in cell and developmental biology · 2021Review
- The HD-Domain Metalloprotein Superfamily: An Apparent Common Protein Scaffold with Diverse Chemistries.Catalysts (Basel, Switzerland) · 2020Article
- A Novel, Pan-PDE Inhibitor Exerts Anti-Fibrotic Effects in Human Lung Fibroblasts via Inhibition of TGF-β Signaling and Activation of cAMP/PKA Signaling.International journal of molecular sciences · 2020Article
- Discovery of novel PDE9A inhibitors with antioxidant activities for treatment of Alzheimer's disease.Journal of enzyme inhibition and medicinal chemistry · 2018Article
- Crystal Structures of Candida albicans Phosphodiesterase 2 and Implications for Its Biological Functions.Biochemistry · 2018Article
- Article
- Structure-based design, synthesis, and biological evaluation of novel pyrimidinone derivatives as PDE9 inhibitors.Acta pharmaceutica Sinica. B · 2018Article
- PDE8 Is Expressed in Human Airway Smooth Muscle and Selectively Regulates cAMP Signaling by βAmerican journal of respiratory cell and molecular biology · 2018Article
- Channeling of cAMP in PDE-PKA Complexes Promotes Signal Adaptation.Biophysical journal · 2017Article
- PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells.Endocrine · 2015Article
Corrections and comments
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Cyclic nucleotide phosphodiesterase-8 (PDE8) is a family of cAMP-specific enzymes and plays important roles in many biological processes, including T-cell activation, testosterone production, adrenocortical hyperplasia, and thyroid function. However, no PDE8 selective inhibitors are available for trial treatment of human diseases. Here we report kinetic properties of the highly active PDE8A1 catalytic domain prepared from refolding and its crystal structures in the unliganded and 3-isobutyl-1-methylxanthine (IBMX) bound forms at 1.9 and 2.1 A resolutions, respectively. The PDE8A1 catalytic domain has a K(M) of 1.8 microM, V(max) of 6.1 micromol/min/mg, a k(cat) of 4.0 s(-1) for cAMP, and a K(M) of 1.6 mM, V(max) of 2.5 micromol/min/mg, a k(cat) of 1.6 s(-1) for cGMP, thus indicating that the substrate specificity of PDE8 is dominated by K(M). The structure of the PDE8A1 catalytic domain has similar topology as those of other PDE families but contains two extra helices around Asn685-Thr710. Since this fragment is distant from the active site of the enzyme, its impact on the catalysis is unclear. The PDE8A1 catalytic domain is insensitive to the IBMX inhibition (IC(50) = 700 microM). The unfavorable interaction of IBMX in the PDE8A1-IBMX structure suggests an important role of Tyr748 in the inhibitor binding. Indeed, the mutation of Tyr748 to phenylalanine increases the PDE8A1 sensitivity to several nonselective or family selective PDE inhibitors. Thus, the structural and mutagenesis studies provide not only insight into the enzymatic properties but also guidelines for design of PDE8 selective inhibitors.
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Registered trials
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