ArticleProceedings of the National Academy of Sciences of the United States of America2014
SuperBiHelix method for predicting the pleiotropic ensemble of G-protein-coupled receptor conformations.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2014. 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.
- Bitter taste TAS2R14 and TAS2R46 receptors bound to G proteins: comparison of cryo-EM, AlphaFold, and molecular dynamics structures.European biophysics journal : EBJ · 2026Article
- The atomistic Mechanism Underlying Regulation of the GPA1 G Protein Signaling Pathway Mediated by Abscisic Acid (ABA) Phytohormone Binding to the GCR1 Plant G Protein Coupled Receptor.Journal of chemical information and modeling · 2026Article
- Agonist activation to open the Gα subunit of the GPCR-G protein precoupled complex defines functional agonist activation of TAS2R5.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Steviol rebaudiosides bind to four different sites of the human sweet taste receptor (T1R2/T1R3) complex explaining confusing experiments.Communications chemistry · 2024Article
- Article
- Ligand-Dependent and G Protein-Dependent Properties for the Sweet Taste Heterodimer, TAS1R2/1R3.The journal of physical chemistry. B · 2024Article
- Predicted structure and cell signaling of TAS2R14 reveal receptor hyper-flexibility for detecting diverse bitter tastes.iScience · 2023Article
- 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
- Design, Synthesis, and Biological Evaluation of a Series of 5- and 7-Hydroxycoumarin Derivatives as 5-HTPharmaceuticals (Basel, Switzerland) · 2021Article
- The G protein-first activation mechanism of opioid receptors by Gi protein and agonists.QRB discovery · 2021Article
- Predicted structure of fully activated human bitter taste receptor TAS2R4 complexed with G protein and agonists.QRB discovery · 2021Article
- Mechanism of β-arrestin recruitment by the μ-opioid G protein-coupled receptor.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- The atomistic level structure for the activated human κ-opioid receptor bound to the full Gi protein and the MP1104 agonist.Proceedings of the National Academy of Sciences of the United States of America · 2020Article
- Improving virtual screening of G protein-coupled receptors via ligand-directed modeling.PLoS computational biology · 2017Article
- 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
- G protein-coupled odorant receptors: From sequence to structure.Protein science : a publication of the Protein Society · 2015Article
- Nullspace Sampling with Holonomic Constraints Reveals Molecular Mechanisms of Protein Gαs.PLoS computational biology · 2015Article
- 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
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5 authors.
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Abstract
There is overwhelming evidence that G-protein-coupled receptors (GPCRs) exhibit several distinct low-energy conformations, each of which might favor binding to different ligands and/or lead to different downstream functions. Understanding the function of such proteins requires knowledge of the ensemble of low-energy configurations that might play a role in this pleiotropic functionality. We earlier reported the BiHelix method for efficiently sampling the (12)(7) = 35 million conformations resulting from 30° rotations about the axis (η) of all seven transmembrane helices (TMHs), showing that the experimental structure is reliably selected as the best conformation from this ensemble. However, various GPCRs differ sufficiently in the tilts of the TMHs that this method need not predict the optimum conformation starting from any other template. In this paper, we introduce the SuperBiHelix method in which the tilt angles (θ, ϕ) are optimized simultaneously with rotations (η) efficiently enough that it is practical and sufficient to sample (5 × 3 × 5)(7) = 13 trillion configurations. This method can correctly identify the optimum structure of a GPCR starting with the template from a different GPCR. We have validated this method by predicting known crystal structure conformations starting from the template of a different protein structure. We find that the SuperBiHelix conformational ensemble includes the higher energy conformations associated with the active protein in addition to those associated with the more stable inactive protein. This methodology was then applied to design and experimentally confirm structures of three mutants of the CB1 cannabinoid receptor associated with different functions.
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