ArticleProtein science : a publication of the Protein Society2013
Molecular basis for dramatic changes in cannabinoid CB1 G protein-coupled receptor activation upon single and double point mutations.
Article in Protein science : a publication of the Protein Society, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- Cardiovascular Effects of Cannabidiol: From Molecular Mechanisms to Clinical Implementation.International journal of molecular sciences · 2025Review
- Methotrexate Inhibits the Binding of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Receptor Binding Domain to the Host-Cell Angiotensin-Converting Enzyme-2 (ACE-2) Receptor.ACS pharmacology & translational science · 2024Article
- Structural Elements Directing G Proteins and β-Arrestin Interactions with the Human Melatonin Type 2 Receptor Revealed by Natural Variants.ACS pharmacology & translational science · 2022Article
- Development of enhanced conformational sampling methods to probe the activation landscape of GPCRs.Advances in protein chemistry and structural biology · 2022Review
- 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
- Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists.QRB discovery · 2021Article
- A novel bioassay for quantification of surface Cannabinoid receptor 1 expression.Scientific reports · 2020Article
- Probing thermostability of detergent-solubilized CBThe Journal of biological chemistry · 2020Article
- Understanding G Protein Selectivity of Muscarinic Acetylcholine Receptors Using Computational Methods.International journal of molecular sciences · 2019Article
- The F238L Point Mutation in the Cannabinoid Type 1 Receptor Enhances Basal Endocytosis via Lipid Rafts.Frontiers in molecular neuroscience · 2018Article
- The G protein GThe Journal of biological chemistry · 2017Article
- Activation mechanism of the G protein-coupled sweet receptor heterodimer with sweeteners and allosteric agonists.Proceedings of the National Academy of Sciences of the United States of America · 2017Article
- Conformational and Thermodynamic Landscape of GPCR Activation from Theory and Computation.Biophysical journal · 2016Article
- Structure-Based Sequence Alignment of the Transmembrane Domains of All Human GPCRs: Phylogenetic, Structural and Functional Implications.PLoS computational biology · 2016Article
- Computational Prediction and Biochemical Analyses of New Inverse Agonists for the CB1 Receptor.Journal of chemical information and modeling · 2016Article
- Minireview: From the bench, toward the clinic: therapeutic opportunities for cannabinoid receptor modulation.Molecular endocrinology (Baltimore, Md.) · 2015Review
- Ligand- and mutation-induced conformational selection in the CCR5 chemokine G protein-coupled receptor.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- SuperBiHelix method for predicting the pleiotropic ensemble of G-protein-coupled receptor conformations.Proceedings of the National Academy of Sciences of the United States of America · 2014Article
- Molecular basis of cannabinoid CB1 receptor coupling to the G protein heterotrimer Gαiβγ: identification of key CB1 contacts with the C-terminal helix α5 of Gαi.The Journal of biological chemistry · 2013Article
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5 authors.
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Abstract
There is considerable interest in determining the activation mechanism of G protein-coupled receptors (GPCRs), one of the most important types of proteins for intercellular signaling. Recently, it was demonstrated for the cannabinoid CB1 GPCR, that a single mutation T210A could make CB1 completely inactive whereas T210I makes it essentially constitutively active. To obtain an understanding of this dramatic dependence of activity on mutation, we used first-principles-based methods to predict the ensemble of low-energy seven-helix conformations for the wild-type (WT) and mutants (T210A and T210I). We find that the transmembrane (TM) helix packings depend markedly on these mutations, leading for T210A to both TM3+TM6 and TM2+TM6 salt-bridge couplings in the cytoplasmic face that explains the inactivity of this mutant. In contrast T210I has no such couplings across the receptor explaining the ease in activating this mutant. WT has just the TM3+TM6 coupling, known to be broken upon GPCR activation. To test this hypothesis on activity, we predicted double mutants that would convert the inactive mutant to normal activity and then confirmed this experimentally. This CB1 activation mechanism, or one similar to it, is expected to play a role in other constitutively active GPCRs as well.
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