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- EMDB-61913: Focused map of Human Lysophosphatidic Acid Receptor 1-Gi complex ... -

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Basic information

Entry
Database: EMDB / ID: EMD-61913
TitleFocused map of Human Lysophosphatidic Acid Receptor 1-Gi complex bound to CpY
Map data
Sample
  • Complex: Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556
    • Complex: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Complex: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Complex: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: Lysophosphatidic Acid Receptor 1
    • Complex: scFv16
KeywordsGPCR / MEMBRANE PROTEIN
Biological speciesRattus norvegicus (Norway rat) / Homo sapiens (human) / Bos taurus (domestic cattle) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.12 Å
AuthorsAkasaka H / Shihoya W / Nureki O
Funding support Japan, 1 items
OrganizationGrant numberCountry
Japan Society for the Promotion of Science (JSPS)21H05037 Japan
CitationJournal: Commun Biol / Year: 2024
Title: Structural mechanisms of potent lysophosphatidic acid receptor 1 activation by nonlipid basic agonists.
Authors: Hiroaki Akasaka / Fumiya K Sano / Wataru Shihoya / Osamu Nureki /
Abstract: Lysophosphatidic acid receptor 1 (LPA) is one of the G protein-coupled receptors activated by the lipid mediator, lysophosphatidic acid (LPA). LPA is associated with a variety of diseases, and LPA ...Lysophosphatidic acid receptor 1 (LPA) is one of the G protein-coupled receptors activated by the lipid mediator, lysophosphatidic acid (LPA). LPA is associated with a variety of diseases, and LPA agonists have potential therapeutic value for treating obesity and depression. Although potent nonlipid LPA agonists have recently been identified, the mechanisms of nonlipid molecule-mediated LPA activation remain unclear. Here, we report a cryo-electron microscopy structure of the human LPA-G complex bound to a nonlipid basic agonist, CpY, which has 30-fold higher agonistic activity as compared with LPA. Structural comparisons of LPA with other lipid GPCRs revealed that the negative charge in the characteristic binding pocket of LPA allows the selective recognition of CpY, which lacks a polar head. In addition, our structure show that the ethyl group of CpY directly pushes W271 to fix the active conformation. Endogenous LPA lacks these chemical features, which thus represent the crucial elements of nonlipid agonists that potently activate LPA. This study provides detailed mechanistic insights into the ligand recognition and activation of LPA by nonlipid agonists, expanding the scope for drug development targeting the LPA receptors.
History
DepositionOct 14, 2024-
Header (metadata) releaseNov 27, 2024-
Map releaseNov 27, 2024-
UpdateNov 27, 2024-
Current statusNov 27, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_61913.png

Downloads & links

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Map

FileDownload / File: emd_61913.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.16 Å/pix.
x 200 pix.
= 232.4 Å		1.16 Å/pix.
x 200 pix.
= 232.4 Å		1.16 Å/pix.
x 200 pix.
= 232.4 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.162 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.8
Minimum - Maximum-7.059213 - 7.8409452
Average (Standard dev.)-0.00016722058 (±0.099249594)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 232.4 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_61913_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_61913_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_61913_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556

EntireName: Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556
Components
  • Complex: Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556
    • Complex: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Complex: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Complex: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Complex: Lysophosphatidic Acid Receptor 1
    • Complex: scFv16

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Supramolecule #1: Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556

SupramoleculeName: Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5

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Supramolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

SupramoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: complex / ID: 2 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Rattus norvegicus (Norway rat)

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Supramolecule #3: Guanine nucleotide-binding protein G(i) subunit alpha-1

SupramoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

SupramoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: complex / ID: 4 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: Bos taurus (domestic cattle)

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Supramolecule #5: Lysophosphatidic Acid Receptor 1

SupramoleculeName: Lysophosphatidic Acid Receptor 1 / type: complex / ID: 5 / Parent: 1 / Macromolecule list: #4
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #6: scFv16

SupramoleculeName: scFv16 / type: complex / ID: 6 / Parent: 1 / Macromolecule list: #5
Source (natural)Organism: Mus musculus (house mouse)

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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

Concentration7 mg/mL
BufferpH: 8
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7dh5

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.12 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 277596
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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