ArticleNature structural & molecular biology2017
Structural basis for the cooperative allosteric activation of the free fatty acid receptor GPR40.
Article in Nature structural & molecular biology, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 107 papers.
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Who cites it
107 citing papers in PubMed, 194 citations in OpenAlex.
- Atomic, structural and molecular insights into GPCR ligand binding and signalling.Nature reviews. Molecular cell biology · 2026Review
- Molecular insights into ago-allosteric modulation at cysteinyl leukotriene receptor 2.Nature communications · 2025Article
- Pla2g7 regulates bone homeostasis via Alox12/12-HETE/Gpr31 signaling axis.Nature communications · 2025Article
- Effect of a Low Electrostatic Environment on the Helical Structures of Peptides and Proteins Using Flexible Water Models: An In Silico Study.ACS omega · 2025Article
- Bitopic AJournal of medicinal chemistry · 2025Article
- Effects of Membrane Cholesterol on the Structure and Function of Selected Class A GPCRs─Challenges and Future Perspectives.Biochemistry · 2025Review
- Effects of chemosynthetic choline plasmalogens on gonadotropin secretion from bovine gonadotrophs.The Journal of reproduction and development · 2025Article
- Cryo-EM reveals an extrahelical allosteric binding site at the MNature communications · 2025Article
- Multicolored sequential resonance energy transfer for detection of simultaneous ligand binding at G protein-coupled receptors.Nature communications · 2025Article
- Article
- Functional dynamics of G protein-coupled receptors reveal new routes for drug discovery.Nature reviews. Drug discovery · 2025Review
- Large scale investigation of GPCR molecular dynamics data uncovers allosteric sites and lateral gateways.Nature communications · 2025Article
- Molecular simulations reveal intricate coupling between agonist-bound β-adrenergic receptors and G protein.iScience · 2025Article
- A non-canonical mechanism of GPCR activation.Nature communications · 2024Article
- Influence of the Water Model on the Structure and Interactions of the GPR40 Protein with the Lipid Membrane and the Solvent: Rigid versus Flexible Water Models.Journal of chemical theory and computation · 2024Article
- G Protein-Coupled Receptor-Ligand Pose and Functional Class Prediction.International journal of molecular sciences · 2024Article
- Structure-based identification of a G protein-biased allosteric modulator of cannabinoid receptor CB1.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Cryo-electron microscopy for GPCR research and drug discovery in endocrinology and metabolism.Nature reviews. Endocrinology · 2024Review
- Identifying and Assessing Putative Allosteric Sites and Modulators for CXCR4 Predicted through Network Modeling and Site Identification by Ligand Competitive Saturation.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
47 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
34 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Clinical studies indicate that partial agonists of the G-protein-coupled, free fatty acid receptor 1 GPR40 enhance glucose-dependent insulin secretion and represent a potential mechanism for the treatment of type 2 diabetes mellitus. Full allosteric agonists (AgoPAMs) of GPR40 bind to a site distinct from partial agonists and can provide additional efficacy. We report the 3.2-Å crystal structure of human GPR40 (hGPR40) in complex with both the partial agonist MK-8666 and an AgoPAM, which exposes a novel lipid-facing AgoPAM-binding pocket outside the transmembrane helical bundle. Comparison with an additional 2.2-Å structure of the hGPR40-MK-8666 binary complex reveals an induced-fit conformational coupling between the partial agonist and AgoPAM binding sites, involving rearrangements of the transmembrane helices 4 and 5 (TM4 and TM5) and transition of the intracellular loop 2 (ICL2) into a short helix. These conformational changes likely prime GPR40 to a more active-like state and explain the binding cooperativity between these ligands.
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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.