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- EMDB-34098: Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-07... -

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Basic information

Entry
Database: EMDB / ID: EMD-34098
TitleHuman Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556, focused on receptor
Map data
Sample
  • Complex: Human Lysophosphatidic Acid Receptor 1 bound to ONO-0740556
    • Protein or peptide: Lysophosphatidic acid receptor 1
  • Ligand: [(2~{R})-2-[5-(2-hexylphenyl)pentanoylamino]-3-oxidanyl-propyl] dihydrogen phosphate
Function / homology
Function and homology information


cellular response to 1-oleoyl-sn-glycerol 3-phosphate / lysophosphatidic acid receptor activity / positive regulation of smooth muscle cell chemotaxis / calmodulin dependent kinase signaling pathway / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / negative regulation of cilium assembly / cellular response to oxygen levels / regulation of synaptic vesicle cycle / oligodendrocyte development ...cellular response to 1-oleoyl-sn-glycerol 3-phosphate / lysophosphatidic acid receptor activity / positive regulation of smooth muscle cell chemotaxis / calmodulin dependent kinase signaling pathway / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / negative regulation of cilium assembly / cellular response to oxygen levels / regulation of synaptic vesicle cycle / oligodendrocyte development / corpus callosum development / bleb assembly / regulation of metabolic process / optic nerve development / negative regulation of cAMP-mediated signaling / regulation of postsynaptic neurotransmitter receptor internalization / positive regulation of dendritic spine development / positive regulation of Rho protein signal transduction / activation of phospholipase C activity / GABA-ergic synapse / G-protein alpha-subunit binding / positive regulation of stress fiber assembly / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / myelination / cerebellum development / neurogenesis / cell chemotaxis / dendritic shaft / PDZ domain binding / G protein-coupled receptor activity / adenylate cyclase-activating G protein-coupled receptor signaling pathway / negative regulation of neuron projection development / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / regulation of cell shape / G alpha (i) signalling events / postsynaptic membrane / G alpha (q) signalling events / positive regulation of canonical NF-kappaB signal transduction / dendritic spine / positive regulation of MAPK cascade / endosome / positive regulation of apoptotic process / G protein-coupled receptor signaling pathway / neuronal cell body / glutamatergic synapse / cell surface / plasma membrane / cytoplasm
Similarity search - Function
Lysophosphatidic acid receptor EDG-2 / Lysophosphatidic acid receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
Lysophosphatidic acid receptor 1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.7 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: Nat Commun / Year: 2022
Title: Structure of the active G-coupled human lysophosphatidic acid receptor 1 complexed with a potent agonist.
Authors: Hiroaki Akasaka / Tatsuki Tanaka / Fumiya K Sano / Yuma Matsuzaki / Wataru Shihoya / Osamu Nureki /
Abstract: Lysophosphatidic acid receptor 1 (LPA) is one of the six G protein-coupled receptors activated by the bioactive lipid, lysophosphatidic acid (LPA). LPA is a drug target for various diseases, ...Lysophosphatidic acid receptor 1 (LPA) is one of the six G protein-coupled receptors activated by the bioactive lipid, lysophosphatidic acid (LPA). LPA is a drug target for various diseases, including cancer, inflammation, and neuropathic pain. Notably, LPA agonists have potential therapeutic value for obesity and urinary incontinence. Here, we report a cryo-electron microscopy structure of the active human LPA-G complex bound to ONO-0740556, an LPA analog with more potent activity against LPA. Our structure elucidated the details of the agonist binding mode and receptor activation mechanism mediated by rearrangements of transmembrane segment 7 and the central hydrophobic core. A structural comparison of LPA and other phylogenetically-related lipid-sensing GPCRs identified the structural determinants for lipid preference of LPA. Moreover, we characterized the structural polymorphisms at the receptor-G-protein interface, which potentially reflect the G-protein dissociation process. Our study provides insights into the detailed mechanism of LPA binding to agonists and paves the way toward the design of drug-like agonists targeting LPA.
History
DepositionAug 16, 2022-
Header (metadata) releaseOct 5, 2022-
Map releaseOct 5, 2022-
UpdateOct 5, 2022-
Current statusOct 5, 2022Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_34098.png

Downloads & links

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Map

FileDownload / File: emd_34098.map.gz / Format: CCP4 / Size: 2.4 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.1952 Å
Density
Contour LevelBy AUTHOR: 1.6
Minimum - Maximum-6.6872606 - 8.12047
Average (Standard dev.)-0.006893598 (±0.48195615)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin8310388
Dimensions848488
Spacing848488
CellA: 100.3968 Å / B: 100.3968 Å / C: 105.1776 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_34098_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_34098_half_map_1.map
Projections & Slices
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Histogram

Histogram (log scale)

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Half map: #1

Fileemd_34098_half_map_2.map
Projections & Slices
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Sample components

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

EntireName: Human Lysophosphatidic Acid Receptor 1 bound to ONO-0740556
Components
  • Complex: Human Lysophosphatidic Acid Receptor 1 bound to ONO-0740556
    • Protein or peptide: Lysophosphatidic acid receptor 1
  • Ligand: [(2~{R})-2-[5-(2-hexylphenyl)pentanoylamino]-3-oxidanyl-propyl] dihydrogen phosphate

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

SupramoleculeName: Human Lysophosphatidic Acid Receptor 1 bound to ONO-0740556
type: complex / Chimera: Yes / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Lysophosphatidic acid receptor 1

MacromoleculeName: Lysophosphatidic acid receptor 1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 42.936004 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDAMG AAISTSIPVI SQPQFTAMNE PQCFYNESIA FFYNRSGKHL ATEWNTVSKL VMGLGITVCI FIMLANLLVM VAIYVNRRF HFPIYYLMAN LAAADFFAGL AYFYLMFNTG PNTRRLTVST WLLRQGLIDT SLTASVANLL AIAIERHITV F RMQLHTRM ...String:
DYKDDDDAMG AAISTSIPVI SQPQFTAMNE PQCFYNESIA FFYNRSGKHL ATEWNTVSKL VMGLGITVCI FIMLANLLVM VAIYVNRRF HFPIYYLMAN LAAADFFAGL AYFYLMFNTG PNTRRLTVST WLLRQGLIDT SLTASVANLL AIAIERHITV F RMQLHTRM SNRRVVVVIV VIWTMAIVMG AIPSVGWNCI CDIENCSNMA PLYSDSYLVF WAIFNLVTFV VMVVLYAHIF GY VRQRTMR MSRHSSGPRR NRDTMMSLLK TVVIVLGAFI ICWTPGLVLL LLDVCCPQCD VLAYEKFFLL LAEFNSAMNP IIY SYRDKE MSATFRQILC CQRSENPTGP TEGSDRSASS LNHTILAGVH SNDHSVVENL YFQ

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Macromolecule #2: [(2~{R})-2-[5-(2-hexylphenyl)pentanoylamino]-3-oxidanyl-propyl] d...

MacromoleculeName: [(2~{R})-2-[5-(2-hexylphenyl)pentanoylamino]-3-oxidanyl-propyl] dihydrogen phosphate
type: ligand / ID: 2 / Number of copies: 1 / Formula: K6L
Molecular weightTheoretical: 415.461 Da
Chemical component information

ChemComp-K6L:
[(2~{R})-2-[5-(2-hexylphenyl)pentanoylamino]-3-oxidanyl-propyl] dihydrogen phosphate

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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

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: 0.5 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
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

Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.7 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 181071
FSC plot (resolution estimation)

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