ArticleProceedings of the National Academy of Sciences of the United States of America2022
The mechanism for ligand activation of the GPCR-G protein complex.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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Who cites it
55 citing papers in PubMed, 98 citations in OpenAlex.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- SSTR2 receptor states and cellular metabolism modulateEANM innovation · 2026Article
- G Protein-Mediated Allosteric Modulation of Ligand Binding in Class A GPCRs: Receptor-Ligand-Transducer Ensembles in Disease and Drug Discovery.Pharmaceuticals (Basel, Switzerland) · 2026Review
- Bitter taste TAS2R14 and TAS2R46 receptors bound to G proteins: comparison of cryo-EM, AlphaFold, and molecular dynamics structures.European biophysics journal : EBJ · 2026Article
- Decoupling between activation time and steady-state level in input-output responses.PLoS computational biology · 2026Article
- Activation dynamics of a water-soluble human mu-opioid receptor.The Journal of biological chemistry · 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
- Exploring the Evolving Role of Scopolamine in Pharmacotherapy: From Cognitive Impairment to Neuroplasticity?-A Narrative Review.Molecules (Basel, Switzerland) · 2026Review
- Structural mechanisms underlying distinct binding and activities of 18:0 and 18:1 lysophosphatidic acids at LPA1 receptor.PLoS computational biology · 2026Article
- Unraveling allosteric signaling of G protein-coupled receptors (GPCRs) by single-molecule fluorescence.Biophysical reviews · 2026Review
- A Transferable and Robust Computational Framework for Class A GPCR Activation Free Energies.The journal of physical chemistry letters · 2026Article
- Molecular mechanism of aspartame recognition by the human sweet taste receptor T1R2-T1R3 revealed by homology modeling and molecular dynamics simulations.Journal of computer-aided molecular design · 2026Article
- Fractalkine (Chemokine CX3CL1) Signaling During Placentation and Placental Function.International journal of molecular sciences · 2026Review
- Molecular simulation-based 3D structural construction of olfactory receptor with agonist binding.Journal of computer-aided molecular design · 2025Article
- Systematic metabolite screening identifies functional regulators of the adenosine A2A receptor.Communications chemistry · 2025Article
- Article
- GPR107: A key driver of breast cancer invasion and metastasis through collagen IV modulation.Cancer gene therapy · 2025Article
- Conformational Signatures of Preassembled and Active Complexes of 5-HTJournal of chemical information and modeling · 2025Article
- Systemic sclerosis, main culprits and involved signaling pathways.Inflammation research : official journal of the European Histamine Research Society ... [et al.] · 2025Review
- Targeting the CCL5/CCR5 axis in tumor-stromal crosstalk to overcome cisplatin resistance in neuroendocrine prostate cancer.Journal of experimental & clinical cancer research : CR · 2025Article
Corrections and comments
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Authors and funding
3 authors at 1 institution in 2 countries.
Funding
Abstract
G protein–coupled receptors (GPCRs) activate cellular responses ranging from odorants to neurotransmitters. Binding an agonist leads to activation of a heterotrimeric G protein (GP) that stimulates external signaling. Unfortunately, the mechanism remains unknown. We show for 15 class A GPCRs, including opioids, adrenergics, adenosines, chemokines, muscarinics, cannabinoids, serotonins, and dopamines, that interaction of an inactive GP, including Gs, Gi, Go, G11, and Gq, to the inactive GPCR, containing the intracellular ionic lock between transmembrane (TM) helices 3 and 6, evolves exothermically to form a precoupled GPCR-GP complex with an opened TM3-TM6 and the GP-α5 helix partially inserted into the GPCR but not activated. We show that binding of agonist to this precoupled GPCR-GP complex causes the Gα protein to open into its active form, with the guanosine diphosphate exposed for signaling. This GP-first paradigm provides a strategy for developing selective agonists for GPCRs since it is the pharmacophore for the precoupled GPCR-GP complex that should be used to design drugs.
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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.