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.
Export Options
About this article
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 |
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Nucleosides, a Valuable Chemical Marker for Quality Control in Traditional Chinese Medicine Cordyceps
Recent Patents on Biotechnology Drug-Induced Pulmonary Hypertension in Newborns: A Review.
Current Vascular Pharmacology A Practical Guide for the Treatment of Symptomatic Heart Failure with Reduced Ejection Fraction (HFrEF)
Current Cardiology Reviews Resveratrol and Lifespan in Model Organisms
Current Medicinal Chemistry Magnesium Lithospermate B Extracted from Salvia Miltiorrhiza, A Potential Substitute for Cardiac Glycosides
Mini-Reviews in Organic Chemistry Diabetic Retinopathy and Atherosclerosis: is there a Link?
Current Diabetes Reviews IL-1 Cytokines in Cardiovascular Disease: Diagnostic, Prognostic and Therapeutic Implications
Cardiovascular & Hematological Agents in Medicinal Chemistry The Risks and Benefits of Therapy with Aldosterone Receptor Antagonist Therapy
Current Drug Safety 5-Adenosine Monophosphate-Activated Protein Kinase and the Metabolic Syndrome
Endocrine, Metabolic & Immune Disorders - Drug Targets Structure-Activity Relationships of Flavonoids
Current Organic Chemistry Role of PI3 Kinase Gamma in Excitation-Contraction Coupling and Heart Disease
Cardiovascular & Hematological Disorders-Drug Targets Parenchymal Injuries
Current Respiratory Medicine Reviews DNA Methylation, An Epigenetic Mode of Gene Expression Regulation in Reproductive Science
Current Pharmaceutical Design Editorial (Thematic Issue: The Coronary Collateral Circulation – Past, Present and Future)
Current Cardiology Reviews NO News is not Necessarily Good News in Cancer
Current Cancer Drug Targets Atrial Fibrillation and Chronic Kidney Disease in Hypertension: A Common and Dangerous Triad
Current Vascular Pharmacology Stem Cell Differentiation Stage Factors from Zebrafish Embryo: A Novel Strategy to Modulate the Fate of Normal and Pathological Human (Stem) Cells
Current Pharmaceutical Biotechnology Impact of Computational Structure-Based Predictive Toxicology in Drug Discovery
Combinatorial Chemistry & High Throughput Screening Development and Engineering of Lymphatic Endothelial Cells: Clinical Implications
Current Pharmaceutical Design HCN Pacemaker Channels and Pain: A Drug Discovery Perspective
Current Pharmaceutical Design