ArticleProceedings of the National Academy of Sciences of the United States of America2015
Engineered stabilization and structural analysis of the autoinhibited conformation of PDE4.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 35 papers.
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Who cites it
35 citing papers in PubMed, 79 citations in OpenAlex.
- Establishing PDE4 as a Novel Target of Urolithin-A in Mitigating LPS-induced Inflammation in Retinal Pigmented Epithelium Cells.Pharmaceutical research · 2025Article
- The Molecular Mechanism of PDE1 Regulation.Cells · 2025Article
- PDE4-Selective Inhibition in Chronic Obstructive Pulmonary Disease and Pulmonary Fibrosis: Different Agents or Different Targets?Life (Basel, Switzerland) · 2025Review
- Chemical, Biochemical, and Structural Similarities and Differences of Dermatological cAMP Phosphodiesterase-IV Inhibitors.The Journal of investigative dermatology · 2025Article
- Targeting Phosphodiesterase 4 in Gastrointestinal and Liver Diseases: From Isoform-Specific Mechanisms to Precision Therapeutics.Biomedicines · 2025Review
- Cyclic nucleotide phosphodiesterases as drug targets.Pharmacological reviews · 2025Review
- Nanodomain cAMP signaling in cardiac pathophysiology: potential for developing targeted therapeutic interventions.Physiological reviews · 2025Review
- Review
- 3D-QSAR Studies on High-affinity Phosphodiestera.Current medicinal chemistry · 2025Article
- Case Report: The widening genetic and phenotypic spectrum of ultra-rare PDE4D-related acroscyphodysplasia.Frontiers in medicine · 2025Article
- PDE4B Missense Variant Increases Susceptibility to Post-traumatic Stress Disorder-Relevant Phenotypes in Mice.The Journal of neuroscience : the official journal of the Society for Neuroscience · 2024Article
- Phosphodiesterase in heart and vessels: from physiology to diseases.Physiological reviews · 2024Review
- Phosphodiesterase 4D activity in acrodysostosis-associated neural pathology: too much or too little?Brain communications · 2024Review
- The evolution of small molecule enzyme activators.RSC medicinal chemistry · 2023Review
- An Empirical Quantitative Structure-Activity Relationship Equation Assists the Discovery of High-Affinity Phosphodiesterase 4D Inhibitors as Leads to PET Radioligands.Journal of medicinal chemistry · 2023Article
- Molecular and thermodynamic mechanisms for protein adaptation.European biophysics journal : EBJ · 2022Review
- Mice Lacking the cAMP Effector Protein POPDC1 Show Enhanced Hippocampal Synaptic Plasticity.Cerebral cortex (New York, N.Y. : 1991) · 2022Article
- Induced pluripotent stem cell-derived mesenchymal stem cells deliver exogenous miR-105-5p via small extracellular vesicles to rejuvenate senescent nucleus pulposus cells and attenuate intervertebral disc degeneration.Stem cell research & therapy · 2021Article
- Insight into Inhibitory Mechanism of PDE4D by Dietary Polyphenols Using Molecular Dynamics Simulations and Free Energy Calculations.Biomolecules · 2021Article
- Shortened Fingers and Toes: GNAS Abnormalities are Not the Only Cause.Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association · 2020Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Phosphodiesterase 4 (PDE4) is an essential contributor to intracellular signaling and an important drug target. The four members of this enzyme family (PDE4A to -D) are functional dimers in which each subunit contains two upstream conserved regions (UCR), UCR1 and -2, which precede the C-terminal catalytic domain. Alternative promoters, transcriptional start sites, and mRNA splicing lead to the existence of over 25 variants of PDE4, broadly classified as long, short, and supershort forms. We report the X-ray crystal structure of long form PDE4B containing UCR1, UCR2, and the catalytic domain, crystallized as a dimer in which a disulfide bond cross-links cysteines engineered into UCR2 and the catalytic domain. Biochemical and mass spectrometric analyses showed that the UCR2-catalytic domain interaction occurs in trans, and established that this interaction regulates the catalytic activity of PDE4. By elucidating the key structural determinants of dimerization, we show that only long forms of PDE4 can be regulated by this mechanism. The results also provide a structural basis for the long-standing observation of high- and low-affinity binding sites for the prototypic inhibitor rolipram.
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