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- EMDB-25819: Lysophosphatidic acid receptor 1-Gi complex bound to LPA -

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Basic information

Entry
Database: EMDB / ID: EMD-25819
TitleLysophosphatidic acid receptor 1-Gi complex bound to LPA
Map data
Sample
  • Complex: complex of Lysophosphatidic Acid Receptor 1 with G-protein and LPA
    • Protein or peptide: Lysophosphatidic acid receptor 1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Ligand: (2R)-2-hydroxy-3-(phosphonooxy)propyl (9E)-octadec-9-enoate
KeywordsGPCR / complex / lipid / MEMBRANE PROTEIN
Function / homology
Function and homology information


Adenylate cyclase inhibitory pathway / adenylate cyclase inhibitor activity / cellular response to 1-oleoyl-sn-glycerol 3-phosphate / lysophosphatidic acid receptor activity / positive regulation of smooth muscle cell chemotaxis / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / Extra-nuclear estrogen signaling ...Adenylate cyclase inhibitory pathway / adenylate cyclase inhibitor activity / cellular response to 1-oleoyl-sn-glycerol 3-phosphate / lysophosphatidic acid receptor activity / positive regulation of smooth muscle cell chemotaxis / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / Extra-nuclear estrogen signaling / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / G alpha (i) signalling events / negative regulation of cilium assembly / corpus callosum development / bleb assembly / oligodendrocyte development / Activation of the phototransduction cascade / cellular response to oxygen levels / negative regulation of cAMP/PKA signal transduction / regulation of synaptic vesicle cycle / regulation of metabolic process / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / optic nerve development / positive regulation of dendritic spine development / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of Rho protein signal transduction / regulation of postsynaptic neurotransmitter receptor internalization / G-protein alpha-subunit binding / negative regulation of insulin secretion / positive regulation of protein localization to cell cortex / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / positive regulation of stress fiber assembly / adenylate cyclase-inhibiting serotonin receptor signaling pathway / neurogenesis / myelination / cellular response to forskolin / cerebellum development / regulation of mitotic spindle organization / dendritic shaft / GABA-ergic synapse / PDZ domain binding / cell chemotaxis / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / adenylate cyclase-activating G protein-coupled receptor signaling pathway / photoreceptor disc membrane / GDP binding / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of taste / signaling receptor complex adaptor activity / regulation of cell shape / presynaptic membrane / negative regulation of neuron projection development / G protein activity / GTPase binding / positive regulation of cytosolic calcium ion concentration / retina development in camera-type eye / midbody / cell cortex / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events
Similarity search - Function
Lysophosphatidic acid receptor EDG-2 / Lysophosphatidic acid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit ...Lysophosphatidic acid receptor EDG-2 / Lysophosphatidic acid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(i) subunit alpha-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Lysophosphatidic acid receptor 1
Similarity search - Component
Biological speciesBos taurus (domestic cattle) / Homo sapiens (human) / Rattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.83 Å
AuthorsLiu S / Paknejad N
Funding support United States, 3 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM138676 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM132307 United States
National Institutes of Health/National Cancer Institute (NIH/NCI)CA243235 United States
CitationJournal: Nat Commun / Year: 2022
Title: Differential activation mechanisms of lipid GPCRs by lysophosphatidic acid and sphingosine 1-phosphate.
Authors: Shian Liu / Navid Paknejad / Lan Zhu / Yasuyuki Kihara / Manisha Ray / Jerold Chun / Wei Liu / Richard K Hite / Xin-Yun Huang /
Abstract: Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). ...Lysophospholipids are bioactive lipids and can signal through G-protein-coupled receptors (GPCRs). The best studied lysophospholipids are lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). The mechanisms of lysophospholipid recognition by an active GPCR, and the activations of lysophospholipid GPCR-G-protein complexes remain unclear. Here we report single-particle cryo-EM structures of human S1P receptor 1 (S1P) and heterotrimeric G complexes formed with bound S1P or the multiple sclerosis (MS) treatment drug Siponimod, as well as human LPA receptor 1 (LPA) and G complexes in the presence of LPA. Our structural and functional data provide insights into how LPA and S1P adopt different conformations to interact with their cognate GPCRs, the selectivity of the homologous lipid GPCRs for S1P versus LPA, and the different activation mechanisms of these GPCRs by LPA and S1P. Our studies also reveal specific optimization strategies to improve the MS-treating S1P-targeting drugs.
History
DepositionDec 30, 2021-
Header (metadata) releaseFeb 9, 2022-
Map releaseFeb 9, 2022-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 4
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 4
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7td0
  • Surface level: 4
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_25819.png

Downloads & links

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Map

FileDownload / File: emd_25819.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
1.06 Å/pix.
x 256 pix.
= 272.384 Å		1.06 Å/pix.
x 256 pix.
= 272.384 Å		1.06 Å/pix.
x 256 pix.
= 272.384 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.064 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 2.0 / Movie #1: 4
Minimum - Maximum-58.686962000000001 - 74.038605000000004
Average (Standard dev.)-0.0001321452 (±0.96304184)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 272.384 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0641.0641.064
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z272.384272.384272.384
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S321
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-58.68774.039-0.000

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Supplemental data

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Sample components

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Entire : complex of Lysophosphatidic Acid Receptor 1 with G-protein and LPA

EntireName: complex of Lysophosphatidic Acid Receptor 1 with G-protein and LPA
Components
  • Complex: complex of Lysophosphatidic Acid Receptor 1 with G-protein and LPA
    • Protein or peptide: Lysophosphatidic acid receptor 1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Ligand: (2R)-2-hydroxy-3-(phosphonooxy)propyl (9E)-octadec-9-enoate

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Supramolecule #1: complex of Lysophosphatidic Acid Receptor 1 with G-protein and LPA

SupramoleculeName: complex of Lysophosphatidic Acid Receptor 1 with G-protein and LPA
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Bos taurus (domestic cattle)

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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: 39.734605 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DYKDDDDKAA AAAISTSIPV ISQPQFTAMN EPQCFYNESI AFFYNRSGKH LATEWNTVSK LVMGLGITVC IFIMLANLLV MVAIYVNRR FHFPIYYLMA NLAAADFFAG LAYFYLMFNT GPNTRRLTVS TWLLRQGLID TSLTASVANL LAIAIERHIT V FRMQLHTR ...String:
DYKDDDDKAA AAAISTSIPV ISQPQFTAMN EPQCFYNESI AFFYNRSGKH LATEWNTVSK LVMGLGITVC IFIMLANLLV MVAIYVNRR FHFPIYYLMA NLAAADFFAG LAYFYLMFNT GPNTRRLTVS TWLLRQGLID TSLTASVANL LAIAIERHIT V FRMQLHTR MSNRRVVVVI VVIWTMAIVM GAIPSVGWNC ICDIENCSNM APLYSDSYLV FWAIFNLVTF VVMVVLYAHI FG YVRQRTM RMSRHSSGPR RNRDTMMSLL KTVVIVLGAF IICWTPGLVL LLLDVCCPQC DVLAYEKFFL LLAEFNSAMN PII YSYRDK EMSATFRQIL CCQRSENPTG PTEG

UniProtKB: Lysophosphatidic acid receptor 1

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

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 37.41693 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

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

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

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 43.16307 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SSGLEVLFQG PHMASMGCTL SAEDKAAVER SKMIDRNLRE DGEKAAREVK LLLLGAGESG KSTIVKQMKI IHEAGYSEE ECKQYKAVVY SNTIQSIIAI IRAMGRLKID FGDSARADDA RQLFVLAGAA EEGFMTAELA GVIKRLWKDS G VQACFNRS ...String:
MGSSHHHHHH SSGLEVLFQG PHMASMGCTL SAEDKAAVER SKMIDRNLRE DGEKAAREVK LLLLGAGESG KSTIVKQMKI IHEAGYSEE ECKQYKAVVY SNTIQSIIAI IRAMGRLKID FGDSARADDA RQLFVLAGAA EEGFMTAELA GVIKRLWKDS G VQACFNRS REYQLNDSAA YYLNDLDRIA QPNYIPTQQD VLRTRVKTTG IVETHFTFKD LHFKMFDVGA QRSERKKWIH CF EGVTAII FCVALSDYDL VLAEDEEMNR MHESMKLFDS ICNNKWFTDT SIILFLNKKD LFEEKIKKSP LTICYPEYAG SNT YEEAAA YIQCQFEDLN KRKDTKEIYT HFTCATDTKN VQFVFDAVTD VIIKNNLKDC GLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 7.845078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFSAI L

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

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Macromolecule #5: (2R)-2-hydroxy-3-(phosphonooxy)propyl (9E)-octadec-9-enoate

MacromoleculeName: (2R)-2-hydroxy-3-(phosphonooxy)propyl (9E)-octadec-9-enoate
type: ligand / ID: 5 / Number of copies: 1 / Formula: NKP
Molecular weightTheoretical: 436.52 Da
Chemical component information

ChemComp-NKP:
(2R)-2-hydroxy-3-(phosphonooxy)propyl (9E)-octadec-9-enoate

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 28.2 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.83 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 1588791
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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