Structural basis for the ligand recognition and signaling of free fatty acid receptors
Free fatty acid receptors 1 to 4 (FFA1 to FFA4) are class A G protein-coupled receptors (GPCRs). FFA1 to FFA3 share substantial sequence similarity, whereas FFA4 is unrelated. However, FFA1 and FFA4 are activated by long-chain fatty acids, while FFA2 and FFA3 respond to short-chain fatty acids generated by intestinal microbiota. FFA1, FFA2, and FFA4 are potential drug targets for metabolic and inflammatory conditions. Here, we determined the active structures of FFA1 and FFA4 bound to docosahexaenoic acid, FFA4 bound to the synthetic agonist TUG-891, and butyrate-bound FFA2, each complexed with an engineered heterotrimeric Gq protein (miniGq), by cryo-electron microscopy. Together with computational simulations and mutagenesis studies, we elucidated the similarities and differences in the binding modes of fatty acid ligands to their respective GPCRs. Our findings unveiled distinct mechanisms of receptor activation and G protein coupling. We anticipate that these outcomes will facilitate structure-based drug development and underpin future research on this group of GPCRs.
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:10 |
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| Enthalten in: |
Science advances - 10(2024), 2 vom: 12. Jan., Seite eadj2384 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Zhang, Xuan [VerfasserIn] |
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Date Completed 12.01.2024 Date Revised 10.02.2024 published: Print-Electronic UpdateOf: bioRxiv. 2023 Aug 21;:. - PMID 37662198 Citation Status MEDLINE |
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| doi: |
10.1126/sciadv.adj2384 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM366891405 |
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| 500 | |a UpdateOf: bioRxiv. 2023 Aug 21;:. - PMID 37662198 | ||
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| 520 | |a Free fatty acid receptors 1 to 4 (FFA1 to FFA4) are class A G protein-coupled receptors (GPCRs). FFA1 to FFA3 share substantial sequence similarity, whereas FFA4 is unrelated. However, FFA1 and FFA4 are activated by long-chain fatty acids, while FFA2 and FFA3 respond to short-chain fatty acids generated by intestinal microbiota. FFA1, FFA2, and FFA4 are potential drug targets for metabolic and inflammatory conditions. Here, we determined the active structures of FFA1 and FFA4 bound to docosahexaenoic acid, FFA4 bound to the synthetic agonist TUG-891, and butyrate-bound FFA2, each complexed with an engineered heterotrimeric Gq protein (miniGq), by cryo-electron microscopy. Together with computational simulations and mutagenesis studies, we elucidated the similarities and differences in the binding modes of fatty acid ligands to their respective GPCRs. Our findings unveiled distinct mechanisms of receptor activation and G protein coupling. We anticipate that these outcomes will facilitate structure-based drug development and underpin future research on this group of GPCRs | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Fatty Acids, Nonesterified |2 NLM | |
| 650 | 7 | |a Ligands |2 NLM | |
| 650 | 7 | |a Fatty Acids |2 NLM | |
| 700 | 1 | |a Guseinov, Abdul-Akim |e verfasserin |4 aut | |
| 700 | 1 | |a Jenkins, Laura |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Kunpeng |e verfasserin |4 aut | |
| 700 | 1 | |a Tikhonova, Irina G |e verfasserin |4 aut | |
| 700 | 1 | |a Milligan, Graeme |e verfasserin |4 aut | |
| 700 | 1 | |a Zhang, Cheng |e verfasserin |4 aut | |
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