ArticleThe Journal of biological chemistry2009
Dynamically driven ligand selectivity in cyclic nucleotide binding domains.
Article in The Journal of biological chemistry, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 45 papers.
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Who cites it
45 citing papers in PubMed, 75 citations in OpenAlex.
- Aortic disease-linked mutations reveal unexpected convergent allosteric mechanisms of protein kinase G misregulation.Science advances · 2026Article
- Accuracy and Reproducibility of Lipari-Szabo Order Parameters From Molecular Dynamics.The journal of physical chemistry. B · 2024Article
- QSAR models reveal new EPAC-selective allosteric modulators.RSC chemical biology · 2022Article
- Article
- Enhanced cGMP Interactor Rap Guanine Exchange Factor 4 (EPAC2) Expression and Activity in Degenerating Photoreceptors: A Neuroprotective Response?International journal of molecular sciences · 2022Article
- Mutation-Induced Long-Range Allosteric Interactions in the Spike Protein Determine the Infectivity of SARS-CoV-2 Emerging Variants.ACS omega · 2021Article
- The cGMP system in normal and degenerating mouse neuroretina: New proteins with cGMP interaction potential identified by a proteomics approach.Journal of neurochemistry · 2021Article
- Noncanonical protein kinase A activation by oligomerization of regulatory subunits as revealed by inherited Carney complex mutations.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Orthogonal fluorescent chemogenetic reporters for multicolor imaging.Nature chemical biology · 2021Article
- Mechanism of allosteric inhibition in theThe Journal of biological chemistry · 2020Article
- Mechanisms of Specific versus Nonspecific Interactions of Aggregation-Prone Inhibitors and Attenuators.Journal of medicinal chemistry · 2019Article
- Insights into exchange factor directly activated by cAMP (EPAC) as potential target for cancer treatment.Molecular and cellular biochemistry · 2018Review
- Intracellular cAMP Sensor EPAC: Physiology, Pathophysiology, and Therapeutics Development.Physiological reviews · 2018Review
- Millisecond Timescale Motions Connect Amino Acid Interaction Networks in Alpha Tryptophan Synthase.Frontiers in molecular biosciences · 2018Article
- Free energy landscape remodeling of the cardiac pacemaker channel explains the molecular basis of familial sinus bradycardia.The Journal of biological chemistry · 2017Article
- Crystal structure of cGMP-dependent protein kinase Iβ cyclic nucleotide-binding-B domain : Rp-cGMPS complex reveals an apo-like, inactive conformation.FEBS letters · 2017Article
- Mechanism of cAMP Partial Agonism in Protein Kinase G (PKG).The Journal of biological chemistry · 2015Article
- Structure-Activity Relationship Studies of Substituted 2-(Isoxazol-3-yl)-2-oxo-N'-phenyl-acetohydrazonoyl Cyanide Analogues: Identification of Potent Exchange Proteins Directly Activated by cAMP (EPAC) Antagonists.Journal of medicinal chemistry · 2015Article
- Mapping the Hydrogen Bond Networks in the Catalytic Subunit of Protein Kinase A Using H/D Fractionation Factors.Biochemistry · 2015Article
- The future of EPAC-targeted therapies: agonism versus antagonism.Trends in pharmacological sciences · 2015Review
Corrections and comments
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Authors and funding
6 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
One of the mechanisms that minimize the aberrant cross-talk between cAMP- and cGMP-dependent signaling pathways relies on the selectivity of cAMP binding domains (CBDs). For instance, the CBDs of two critical eukaryotic cAMP receptors, i.e. protein kinase A (PKA) and the exchange protein activated by cAMP (EPAC), are both selectively activated by cAMP. However, the mechanisms underlying their cAMP versus cGMP selectivity are quite distinct. In PKA this selectivity is controlled mainly at the level of ligand affinity, whereas in EPAC it is mostly determined at the level of allostery. Currently, the molecular basis for these different selectivity mechanisms is not fully understood. We have therefore comparatively analyzed by NMR the cGMP-bound states of the essential CBDs of PKA and EPAC, revealing key differences between them. Specifically, cGMP binds PKA preserving the same syn base orientation as cAMP at the price of local steric clashes, which lead to a reduced affinity for cGMP. Unlike PKA, cGMP is recognized by EPAC in an anti conformation and generates several short and long range perturbations. Although these effects do not alter significantly the structure of the EPAC CBD investigated, remarkable differences in dynamics between the cAMP- and cGMP-bound states are detected for the ionic latch region. These observations suggest that one of the determinants of cGMP antagonism in EPAC is the modulation of the entropic control of inhibitory interactions and illustrate the pivotal role of allostery in determining signaling selectivity as a function of dynamic changes, even in the absence of significant affinity variations.
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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 OpenQuestion graph.