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- PDB-9j5v: Human Lysophosphatidic Acid Receptor 1-Gi complex bound to CpY -

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Basic information

Entry
Database: PDB / ID: 9j5v
TitleHuman Lysophosphatidic Acid Receptor 1-Gi complex bound to CpY
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Lysophosphatidic acid receptor 1,Lysophosphatidic acid receptor 1,Lysophosphatidic acid receptor 1,LgBiT
  • scFv16
KeywordsMEMBRANE PROTEIN / GPCR
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 / Adenylate cyclase inhibitory pathway / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / negative regulation of cilium assembly / corpus callosum development / bleb assembly / optic nerve development ...cellular response to 1-oleoyl-sn-glycerol 3-phosphate / lysophosphatidic acid receptor activity / positive regulation of smooth muscle cell chemotaxis / Adenylate cyclase inhibitory pathway / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / negative regulation of cilium assembly / corpus callosum development / bleb assembly / optic nerve development / cellular response to oxygen levels / oligodendrocyte development / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / regulation of synaptic vesicle cycle / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / negative regulation of cAMP/PKA signal transduction / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / regulation of metabolic process / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Extra-nuclear estrogen signaling / photoreceptor outer segment membrane / spectrin binding / G alpha (i) signalling events / regulation of postsynaptic neurotransmitter receptor internalization / positive regulation of Rho protein signal transduction / positive regulation of dendritic spine development / alkylglycerophosphoethanolamine phosphodiesterase activity / G-protein alpha-subunit binding / photoreceptor outer segment / positive regulation of protein localization to cell cortex / positive regulation of stress fiber assembly / neurogenesis / cardiac muscle cell apoptotic process / myelination / photoreceptor inner segment / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / cerebellum development / dendritic shaft / cell chemotaxis / PDZ domain binding / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / GDP binding / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / regulation of cell shape / sensory perception of taste / negative regulation of neuron projection development / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs)
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 / G protein beta WD-40 repeat protein / 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. / 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)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Lysophosphatidic acid receptor 1
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Homo sapiens (human)
Bos taurus (domestic cattle)
synthetic construct (others)
Mus musculus (house mouse)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.86 Å
AuthorsAkasaka, H. / Shihoya, W. / Nureki, O.
Funding support Japan, 1items
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
DepositionAug 13, 2024Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 27, 2024Provider: repository / Type: Initial release
Revision 1.0Nov 27, 2024Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Revision 1.1Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
R: Lysophosphatidic acid receptor 1,Lysophosphatidic acid receptor 1,Lysophosphatidic acid receptor 1,LgBiT
S: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)178,9946
Polymers178,7195
Non-polymers2751
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules BGA

#1: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 40470.105 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P54311
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7563.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768
#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40415.031 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63097

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Protein / Antibody / Non-polymers , 3 types, 3 molecules RS

#4: Protein Lysophosphatidic acid receptor 1,Lysophosphatidic acid receptor 1,Lysophosphatidic acid receptor 1,LgBiT / LPA receptor 1 / LPA-1 / Lysophosphatidic acid receptor Edg-2


Mass: 62548.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: LPAR1, EDG2, LPA1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92633
#5: Antibody scFv16


Mass: 27720.795 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#6: Chemical ChemComp-A1L3Q / CpY / (2~{R})-2-(diethylamino)-2-(2-ethyl-3-methyl-1-benzofuran-7-yl)ethanol


Mass: 275.386 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H25NO2 / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

Component
IDNameTypeEntity IDParent-IDSource
1Human Lysophosphatidic Acid Receptor 1-Gi complex bound to ONO-0740556COMPLEX#1-#50MULTIPLE SOURCES
2Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(i) subunit alpha-1COMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#31RECOMBINANT
5Lysophosphatidic Acid Receptor 1COMPLEX#41RECOMBINANT
6scFv16COMPLEX#51RECOMBINANT
Molecular weight
IDEntity assembly-IDExperimental value
11NO
21NO
31NO
41NO
51NO
61NO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Rattus norvegicus (Norway rat)10116
33Homo sapiens (human)9606
44Bos taurus (domestic cattle)9913
55Homo sapiens (human)9606
66Mus musculus (house mouse)10090
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 8
SpecimenConc.: 7 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.86 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 277598 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0078961
ELECTRON MICROSCOPYf_angle_d0.92412155
ELECTRON MICROSCOPYf_dihedral_angle_d4.2281242
ELECTRON MICROSCOPYf_chiral_restr0.041389
ELECTRON MICROSCOPYf_plane_restr0.0041536

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