ArticleProceedings of the National Academy of Sciences of the United States of America2020
DCyFIR: a high-throughput CRISPR platform for multiplexed G protein-coupled receptor profiling and ligand discovery.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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Who cites it
54 citing papers in PubMed, 79 citations in OpenAlex.
- High-throughput DNA engineering by mating bacteria.Cell systems · 2026Article
- G-protein regulatory network governs receptor internalization dynamics.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mining Genetically Encoded Biosensors from Filamentous Fungi.Journal of fungi (Basel, Switzerland) · 2026Review
- Tuning the Response of GPCR-Based Yeast Sensors Using Fluorescent Reporters.ACS synthetic biology · 2026Article
- Immune remodeling and metabolic reprogramming in chronic fatigue: insights into GPCR signaling and epigenetic regulation.Frontiers in immunology · 2026Review
- GPCR signaling systems facilitate precision interventions for multi-oncology therapy.Frontiers in systems biology · 2026Review
- A yeast surface display platform for characterizing CAR T cell responses to cancer antigens.Nature communications · 2025Article
- PIONEER: A Periplasmic Display Platform for Synthetic Biology-Based Screening of Genetically Encoded Protein Regulators.bioRxiv : the preprint server for biology · 2025Article
- The Pharmacological Evidences for the Involvement of AhR and GPR35 Receptors in Kynurenic Acid-Mediated Cytokine and Chemokine Secretion by THP-1-Derived Macrophages.Molecules (Basel, Switzerland) · 2025Article
- Exogenous activation of the adhesion GPCR ADGRD1/GPR133 protects against bone loss by negatively regulating osteoclastogenesis.Science advances · 2025Article
- HCAR3 and Kynurenic Acid in Cancer: A Promising Axis of Immunometabolic Regulation or a Scientific Mirage?International journal of molecular sciences · 2025Review
- Modulating the Properties of GPCR-Based Sensors Via C-Terminus Isoforms.ACS synthetic biology · 2025Article
- Labels as a feature: Network homophily for systematically annotating human GPCR drug-target interactions.Nature communications · 2025Article
- Emerging paradigms for target discovery of traditional medicines: A genome-wide pan-GPCR perspective.Innovation (Cambridge (Mass.)) · 2025Review
- Balancing G protein selectivity and efficacy in the adenosine ANature chemical biology · 2025Article
- Short-chain fatty acids: key antiviral mediators of gut microbiota.Frontiers in immunology · 2025Review
- Loop diuretics inhibit kynurenic acid production and kynurenine aminotransferases activity in rat kidneys.Pharmacological reports : PR · 2024Article
- Genome-wide pan-GPCR cell libraries accelerate drug discovery.Acta pharmaceutica Sinica. B · 2024Review
- The Biology and Biochemistry of Kynurenic Acid, a Potential Nutraceutical with Multiple Biological Effects.International journal of molecular sciences · 2024Review
- The Complex World of Kynurenic Acid: Reflections on Biological Issues and Therapeutic Strategy.International journal of molecular sciences · 2024Review
Corrections and comments
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Authors and funding
7 authors at 2 institutions in 1 country.
Funding
Abstract
More than 800 G protein-coupled receptors (GPCRs) comprise the largest class of membrane receptors in humans. While there is ample biological understanding and many approved drugs for prototypic GPCRs, most GPCRs still lack well-defined biological ligands and drugs. Here, we report our efforts to tap the potential of understudied GPCRs by developing yeast-based technologies for high-throughput clustered regularly interspaced short palindromic repeats (CRISPR) engineering and GPCR ligand discovery. We refer to these technologies collectively as Dynamic Cyan Induction by Functional Integrated Receptors, or DCyFIR. A major advantage of DCyFIR is that GPCRs and other assay components are CRISPR-integrated directly into the yeast genome, making it possible to decode ligand specificity by profiling mixtures of GPCR-barcoded yeast strains in a single tube. To demonstrate the capabilities of DCyFIR, we engineered a yeast strain library of 30 human GPCRs and their 300 possible GPCR-Gα coupling combinations. Profiling of these 300 strains, using parallel (DCyFIRscreen) and multiplex (DCyFIRplex) DCyFIR modes, recapitulated known GPCR agonism with 100% accuracy, and identified unexpected interactions for the receptors ADRA2B, HCAR3, MTNR1A, S1PR1, and S1PR2. To demonstrate DCyFIR scalability, we profiled a library of 320 human metabolites and discovered several GPCR-metabolite interactions. Remarkably, many of these findings pertained to understudied pharmacologically dark receptors GPR4, GPR65, GPR68, and HCAR3. Experiments on select receptors in mammalian cells confirmed our yeast-based observations, including our discovery that kynurenic acid activates HCAR3 in addition to GPR35, its known receptor. Taken together, these findings demonstrate the power of DCyFIR for identifying ligand interactions with prototypic and understudied GPCRs.
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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.