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- EMDB-41014: Cryo-EM structure of the DHA bound FFA1-Gq complex(mask on receptor) -

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Basic information

Entry
Database: EMDB / ID: EMD-41014
TitleCryo-EM structure of the DHA bound FFA1-Gq complex(mask on receptor)
Map dataDHA-FFA1-miniGq-Local
Sample
  • Complex: DHA-FFA1-miniGq complex(mask on receptor)
KeywordsGPCR / Complex / agonist / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsZhang X / Tikhonova I / Milligan G / Zhang C
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM128641 United States
CitationJournal: Sci Adv / Year: 2024
Title: Structural basis for the ligand recognition and signaling of free fatty acid receptors.
Authors: Xuan Zhang / Abdul-Akim Guseinov / Laura Jenkins / Kunpeng Li / Irina G Tikhonova / Graeme Milligan / Cheng Zhang /
Abstract: 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 ...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 G protein (miniG), 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.
History
DepositionJun 7, 2023-
Header (metadata) releaseJan 17, 2024-
Map releaseJan 17, 2024-
UpdateJan 17, 2024-
Current statusJan 17, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_41014.png

Downloads & links

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Map

FileDownload / File: emd_41014.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationDHA-FFA1-miniGq-Local
Voxel sizeX=Y=Z: 0.826 Å
Density
Contour LevelBy AUTHOR: 0.155
Minimum - Maximum-1.1022226 - 1.4728351
Average (Standard dev.)0.0010876213 (±0.030711735)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 211.456 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: DHA-FFA1-miniGq-Local-half B

Fileemd_41014_half_map_1.map
AnnotationDHA-FFA1-miniGq-Local-half_B
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: DHA-FFA1-miniGq-Local-half A

Fileemd_41014_half_map_2.map
AnnotationDHA-FFA1-miniGq-Local-half_A
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : DHA-FFA1-miniGq complex(mask on receptor)

EntireName: DHA-FFA1-miniGq complex(mask on receptor)
Components
  • Complex: DHA-FFA1-miniGq complex(mask on receptor)

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Supramolecule #1: DHA-FFA1-miniGq complex(mask on receptor)

SupramoleculeName: DHA-FFA1-miniGq complex(mask on receptor) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.8 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 61.6 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 305318

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