ArticleThe Journal of biological chemistry2012
Identification of amino acid residues responsible for the selectivity of tadalafil binding to two closely related phosphodiesterases, PDE5 and PDE6.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 35 citations in OpenAlex.
- Mechanism investigation of highly selective inhibitors toward phosphodiesterase 5 and 6 via theFrontiers in chemistry · 2024Article
- The Role of Personalized Medicine in Companion Animal Cardiology.The Veterinary clinics of North America. Small animal practice · 2023Review
- Photoreceptor Phosphodiesterase (PDE6): Structure, Regulatory Mechanisms, and Implications for Treatment of Retinal Diseases.Advances in experimental medicine and biology · 2022Review
- Photoreceptor phosphodiesterase (PDE6): activation and inactivation mechanisms during visual transduction in rods and cones.Pflugers Archiv : European journal of physiology · 2021Review
- A synthetic mimic of phosphodiesterase type 5 based on corona phase molecular recognition of single-walled carbon nanotubes.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Defining the Efficacy and Safety of Phosphodiesterase Type 5 Inhibitors with Tamsulosin for the Treatment of Lower Urinary Tract Symptoms Secondary to Benign Prostatic Hyperplasia with or without Erectile Dysfunction: A Network Meta-Analysis.BioMed research international · 2020Review
- Effect of a phosphodiesterase-5A (PDE5A) gene polymorphism on response to sildenafil therapy in canine pulmonary hypertension.Scientific reports · 2019Article
- Catalytic Domains of Phosphodiesterase 5, 6, and 5/6 Chimera Display Differential Dynamics and Ligand Dissociation Energy Barriers.The journal of physical chemistry. B · 2019Article
- Investigation of PDE5/PDE6 and PDE5/PDE11 selective potent tadalafil-like PDE5 inhibitors using combination of molecular modeling approaches, molecular fingerprint-based virtual screening protocols and structure-based pharmacophore development.Journal of enzyme inhibition and medicinal chemistry · 2017Article
- Mechanisms of mutant PDE6 proteins underlying retinal diseases.Cellular signalling · 2017Article
- Aryl Hydrocarbon Receptor-interacting Protein-like 1 Is an Obligate Chaperone of Phosphodiesterase 6 and Is Assisted by the γ-Subunit of Its Client.The Journal of biological chemistry · 2016Article
- Bilateral visual loss recovering after tadalafil withdrawal.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2016Article
- Phosphodiesterases maintain signaling fidelity via compartmentalization of cyclic nucleotides.Physiology (Bethesda, Md.) · 2014Review
- PDE5 inhibitor drugs for use in dementia.Alzheimer's & dementia (New York, N. Y.)Article
- Identification of PDE5A:E90K: a polymorphism in the canine phosphodiesterase 5A gene affecting basal cGMP concentrations of healthy dogs.Journal of veterinary internal medicineArticle
Corrections and comments
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Authors and funding
4 authors at 2 institutions in 1 country.
Funding
Abstract
The 11 families of the Class I cyclic nucleotide phosphodiesterases (PDEs) are critical for regulation of cyclic nucleotide signaling. PDE5 (important in regulating vascular smooth muscle contraction) and PDE6 (responsible for regulating visual transduction in vertebrate photoreceptors) are structurally similar but have several functional differences whose structural basis is poorly understood. Using evolutionary trace analysis and structural homology modeling in conjunction with site-directed mutagenesis, we have tested the hypothesis that class-specific differences between PDE5 and PDE6 account for the biochemical and pharmacological differences in the two enzyme families. Replacing human PDE5 residues in the M-loop region of the binding site for the PDE5-selective inhibitor tadalafil (Cialis®) with the corresponding class-specific cone PDE6 residues (P773E, I778V, E780L, F787W, E796V, D803P, L804M, N806D, I813L, S815K) reduces tadalafil binding affinity to levels characteristic of PDE6. These mutations fail to alter vardenafil (Levitra®) affinity for the active site. Class-specific differences in PDE5 versus cone PDE6 that contribute to the accelerated catalytic efficiency of PDE6 were identified but required heterologous expression of full-length PDE5 constructs. Introduction of PDE6 residues into the background of the PDE5 protein sequence often led to loss of catalytic activity and reduced protein solubility, supporting the idea that multiple structural elements of PDE6 are highly susceptible to misfolding during heterologous expression. This work validates the use of PDE5 as a template to identify functional differences between PDE5 and PDE6 that will accelerate efforts to develop the next generation of PDE5-selective inhibitors with fewer adverse side effects resulting from PDE6 inhibition.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.