ArticleNature2014
High-resolution structure of the human GPR40 receptor bound to allosteric agonist TAK-875.
Article in Nature, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 138 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
138 citing papers in PubMed, 343 citations in OpenAlex.
- The structure and function of taste G protein-coupled receptors and their implications in diseases.International journal of oral science · 2026Review
- Unraveling allosteric signaling of G protein-coupled receptors (GPCRs) by single-molecule fluorescence.Biophysical reviews · 2026Review
- Computational design of constitutively active mutants of Dopamine D2 receptor inspired by ligand-independent activation mechanisms.BMC biology · 2026Article
- 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
- Multicolored sequential resonance energy transfer for detection of simultaneous ligand binding at G protein-coupled receptors.Nature communications · 2025Article
- G-Protein-Coupled Receptor (GPCR) Signaling and Pharmacology in Metabolism: Physiology, Mechanisms, and Therapeutic Potential.Biomolecules · 2025Review
- Smart control lipid-based nanocarriers for fine-tuning gut hormone secretion.Science advances · 2024Article
- Combined Physics- and Machine-Learning-Based Method to Identify Druggable Binding Sites Using SILCS-Hotspots.Journal of chemical information and modeling · 2024Article
- Integrative residue-intuitive machine learning and MD Approach to Unveil Allosteric Site and Mechanism for β2AR.Nature communications · 2024Article
- Automated design of multi-target ligands by generative deep learning.Nature communications · 2024Article
- ezAlign: A Tool for Converting Coarse-Grained Molecular Dynamics Structures to Atomistic Resolution for Multiscale Modeling.Molecules (Basel, Switzerland) · 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
- 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
- G protein-coupled receptors (GPCRs): advances in structures, mechanisms, and drug discovery.Signal transduction and targeted therapy · 2024Review
- Article
- Structural basis for the ligand recognition and signaling of free fatty acid receptors.Science advances · 2024Article
- A computational and machine learning approach to identify GPR40-targeting agonists for neurodegenerative disease treatment.PloS one · 2024Article
- Recent Developments in Drug Design of Oral Synthetic Free Fatty Acid Receptor 1 Agonists.Drug design, development and therapy · 2024Review
78 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
Abstract
Human GPR40 receptor (hGPR40), also known as free fatty-acid receptor 1 (FFAR1), is a G-protein-coupled receptor that binds long-chain free fatty acids to enhance glucose-dependent insulin secretion. Novel treatments for type-2 diabetes mellitus are therefore possible by targeting hGPR40 with partial or full agonists. TAK-875, or fasiglifam, is an orally available, potent and selective partial agonist of hGPR40 receptor, which reached phase III clinical trials for the potential treatment of type-2 diabetes mellitus. Data from clinical studies indicate that TAK-875, which is an ago-allosteric modulator of hGPR40 (ref. 3), demonstrates improved glycaemic control and low hypoglycaemic risk in diabetic patients. Here we report the crystal structure of hGPR40 receptor bound to TAK-875 at 2.3 Å resolution. The co-complex structure reveals a unique binding mode of TAK-875 and suggests that entry to the non-canonical binding pocket most probably occurs via the lipid bilayer. The atomic details of the extensive charge network in the ligand binding pocket reveal additional interactions not identified in previous studies and contribute to a clear understanding of TAK-875 binding to the receptor. The hGPR40-TAK-875 structure also provides insights into the plausible binding of multiple ligands to the receptor, which has been observed in radioligand binding and Ca(2+) influx assay studies. Comparison of the transmembrane helix architecture with other G-protein-coupled receptors suggests that the crystallized TAK-875-bound hGPR40 complex is in an inactive-like state.
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What OpenQuestion holds
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.