ArticleProteins2013
Computationally-predicted CB1 cannabinoid receptor mutants show distinct patterns of salt-bridges that correlate with their level of constitutive activity reflected in G protein coupling levels, thermal stability, and ligand binding.
Article in Proteins, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 24 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
24 citing papers in PubMed, 43 citations in OpenAlex.
- Activity-restoring mutations in the histamine HProtein science : a publication of the Protein Society · 2026Article
- Cardiovascular Effects of Cannabidiol: From Molecular Mechanisms to Clinical Implementation.International journal of molecular sciences · 2025Review
- Differential Behavior of Conformational Dynamics in Active and Inactive States of Cannabinoid Receptor 1.The journal of physical chemistry. B · 2024Article
- Structural and dynamic insights into the activation of the μ-opioid receptor by an allosteric modulator.Nature communications · 2024Article
- Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes.iScience · 2023Article
- Activation mechanism of the μ-opioid receptor by an allosteric modulator.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.Advances in protein chemistry and structural biology · 2022Review
- Understanding the role of the CB1 toggle switch in interaction networks using molecular dynamics simulation.Scientific reports · 2021Article
- Structures and Agonist Binding Sites of Bitter Taste Receptor TAS2R5 Complexed with Gi Protein and Validated against Experiment.The journal of physical chemistry letters · 2021Article
- Rational design of cannabinoid type-1 receptor allosteric modulators: Org27569 and PSNCBAM-1 hybrids.Bioorganic & medicinal chemistry · 2021Article
- Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists.QRB discovery · 2021Article
- Probing thermostability of detergent-solubilized CBThe Journal of biological chemistry · 2020Article
- Allosteric modulators restore orthosteric agonist binding to mutated CBThe Journal of pharmacy and pharmacology · 2020Article
- Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods.International journal of molecular sciences · 2019Article
- Structural Insights into CB1 Receptor Biased Signaling.International journal of molecular sciences · 2019Review
- Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity.The international journal of neuropsychopharmacology · 2018Review
- The F238L Point Mutation in the Cannabinoid Type 1 Receptor Enhances Basal Endocytosis via Lipid Rafts.Frontiers in molecular neuroscience · 2018Article
- Leveraging allostery to improve G protein-coupled receptor (GPCR)-directed therapeutics: cannabinoid receptor 1 as discovery target.Expert opinion on drug discovery · 2016Review
- Computational analysis of the CB1 carboxyl-terminus in the receptor-G protein complex.Proteins · 2016Article
- Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications.PLoS computational biology · 2016Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
5 authors at 2 institutions in 1 country.
Funding
Abstract
The cannabinoid receptor 1 (CB1), a member of the class A G-protein-coupled receptor (GPCR) family, possesses an observable level of constitutive activity. Its activation mechanism, however, has yet to be elucidated. Previously we discovered dramatic changes in CB1 activity due to single mutations; T3.46A, which made the receptor inactive, and T3.46I and L3.43A, which made it essentially fully constitutively active. Our subsequent prediction of the structures of these mutant receptors indicated that these changes in activity are explained in terms of the pattern of salt-bridges in the receptor region involving transmembrane domains 2, 3, 5, and 6. Here we identified key salt-bridges, R2.37 + D6.30 and D2.63 + K3.28, critical for CB1 inactive and active states, respectively, and generated new mutant receptors that we predicted would change CB1 activity by either precluding or promoting these interactions. We find that breaking the R2.37 + D6.30 salt-bridge resulted in substantial increase in G-protein coupling activity and reduced thermal stability relative to the wild-type reflecting the changes in constitutive activity from inactive to active. In contrast, breaking the D2.63 + K3.28 salt-bridge produced the opposite profile suggesting this interaction is critical for the receptor activation. Thus, we demonstrate an excellent correlation with the predicted pattern of key salt-bridges and experimental levels of activity and conformational flexibility. These results are also consistent with the extended ternary complex model with respect to shifts in agonist and inverse agonist affinity and provide a powerful framework for understanding the molecular basis for the multiple stages of CB1 activation and that of other GPCRs in general.
Indexed as
Identifiers
What OpenQuestion holds
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.