ArticleThe Journal of biological chemistry2013
A constitutively activating mutation alters the dynamics and energetics of a key conformational change in a ligand-free G protein-coupled receptor.
Article in The Journal of biological chemistry, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 43 citations in OpenAlex.
- Article
- Cellular lipids regulate the conformational ensembles of the disordered intracellular loop 3 in β2-adrenergic receptor.iScience · 2024Article
- A rapid, tag-free way to purify functional GPCRs.The Journal of biological chemistry · 2024Article
- Cellular Lipids Regulate the Conformational Ensembles of the Disordered Intracellular Loop 3 in β2 Adrenergic Receptor.bioRxiv : the preprint server for biology · 2023Article
- Ligand-Free Signaling of G-Protein-Coupled Receptors: Physiology, Pharmacology, and Genetics.Molecules (Basel, Switzerland) · 2023Review
- Measuring Membrane Penetration Depths and Conformational Changes in Membrane Peptides and Proteins.The Journal of membrane biology · 2022Review
- FRET sensors reveal the retinal entry pathway in the G protein-coupled receptor rhodopsin.iScience · 2022Article
- Novel fluorescent GPCR biosensor detects retinal equilibrium binding to opsin and active G protein and arrestin signaling conformations.The Journal of biological chemistry · 2020Article
- Activation Microswitches in Adenosine Receptor ABiochemistry · 2020Article
- From extraocular photoreception to pigment movement regulation: a new control mechanism of the lanternshark luminescence.Scientific reports · 2020Article
- Characterization, Dynamics, and Mechanism of CXCR4 Antagonists on a Constitutively Active Mutant.Cell chemical biology · 2019Article
- Site-Directed Fluorescence Approaches for Dynamic Structural Biology of Membrane Peptides and Proteins.Frontiers in molecular biosciences · 2019Review
- Computational Approaches to Prioritize Cancer Driver Missense Mutations.International journal of molecular sciences · 2018Review
- Structural properties determining low KThe Journal of biological chemistry · 2018Article
- A ciliary opsin in the brain of a marine annelid zooplankton is ultraviolet-sensitive, and the sensitivity is tuned by a single amino acid residue.The Journal of biological chemistry · 2017Article
- Nanodiscs in Membrane Biochemistry and Biophysics.Chemical reviews · 2017Review
- Decay of an active GPCR: Conformational dynamics govern agonist rebinding and persistence of an active, yet empty, receptor state.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- Article
- Retinal Attachment Instability Is Diversified among Mammalian Melanopsins.The Journal of biological chemistry · 2015Article
- Structural dynamics and energetics underlying allosteric inactivation of the cannabinoid receptor CB1.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
G protein-coupled receptors (GPCRs) undergo dynamic transitions between active and inactive conformations. Usually, these conversions are triggered when the receptor detects an external signal, but some so-called constitutively activating mutations, or CAMs, induce a GPCR to bind and activate G proteins in the absence of external stimulation, in ways still not fully understood. Here, we investigated how a CAM alters the structure of a GPCR and the dynamics involved as the receptor transitions between different conformations. Our approach used site-directed fluorescence labeling (SDFL) spectroscopy to compare opsin, the ligand-free form of the GPCR rhodopsin, with opsin containing the CAM M257Y, focusing specifically on key movements that occur in the sixth transmembrane helix (TM6) during GPCR activation. The site-directed fluorescence labeling data indicate opsin is constrained to an inactive conformation both in detergent micelles and lipid membranes, but when it contains the M257Y CAM, opsin is more dynamic and can interact with a G protein mimetic. Further study of these receptors using tryptophan-induced quenching (TrIQ) methods indicates that in detergent, the CAM significantly increases the population of receptors in the active state, but not in lipids. Subsequent Arrhenius analysis of the TrIQ data suggests that, both in detergent and lipids, the CAM lowers the energy barrier for TM6 movement, a key transition required for conversion between the inactive and active conformations. Together, these data suggest that the lowered energy barrier is a primary effect of the CAM on the receptor dynamics and energetics.
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