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- PDB-7td1: Lysophosphatidic acid receptor 1-Gi complex bound to LPA, state a -

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Entry
Database: PDB / ID: 7td1
TitleLysophosphatidic acid receptor 1-Gi complex bound to LPA, state a
Components
  • Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
  • Guanine nucleotide-binding protein G(i) subunit alpha-1
  • Lysophosphatidic acid receptor 1
KeywordsMEMBRANE PROTEIN / GPCR / complex / lipid
Function / homology
Function and homology information


Adenylate cyclase inhibitory pathway / 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 / calmodulin dependent kinase signaling pathway / Lysosphingolipid and LPA receptors / lysophosphatidic acid binding / Extra-nuclear estrogen signaling ...Adenylate cyclase inhibitory pathway / 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 / calmodulin dependent kinase signaling pathway / 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) / negative regulation of cilium assembly / G alpha (i) signalling events / regulation of synaptic vesicle cycle / cellular response to oxygen levels / oligodendrocyte development / corpus callosum development / bleb assembly / Activation of the phototransduction cascade / regulation of metabolic process / optic nerve development / negative regulation of cAMP-mediated signaling / regulation of postsynaptic neurotransmitter receptor internalization / negative regulation of synaptic transmission / 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 / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / GTPase activating protein binding / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / positive regulation of dendritic spine development / G alpha (q) signalling events / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / positive regulation of Rho protein signal transduction / Vasopressin regulates renal water homeostasis via Aquaporins / activation of phospholipase C activity / GABA-ergic synapse / positive regulation of protein localization to cell cortex / G-protein alpha-subunit binding / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / positive regulation of stress fiber assembly / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / myelination / cerebellum development / neurogenesis / cell chemotaxis / dendritic shaft / G protein-coupled receptor binding / PDZ domain binding / G protein-coupled receptor activity / G-protein beta/gamma-subunit complex binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / photoreceptor disc membrane / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / sensory perception of taste / GDP binding / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / negative regulation of neuron projection development / retina development in camera-type eye / GTPase binding / presynaptic membrane / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / 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 / cell population proliferation / dendritic spine
Similarity search - Function
Lysophosphatidic acid receptor EDG-2 / Lysophosphatidic acid receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / 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 / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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 / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Chem-NKP / 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 speciesHomo sapiens (human)
Bos taurus (cattle)
Rattus norvegicus (Norway rat)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsLiu, S. / Paknejad, N. / Zhu, L. / Kihara, Y. / Ray, D. / Chun, J. / Liu, W. / Hite, R.K. / Huang, X.Y.
Funding support United States, 3items
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, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 9, 2022Provider: repository / Type: Initial release
Revision 1.1Feb 23, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)128,5965
Polymers128,1604
Non-polymers4371
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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


Mass: 39734.605 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LPAR1, EDG2, LPA1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q92633
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37416.930 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62871
#3: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 43163.070 Da / Num. of mol.: 1 / Mutation: G203A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnai1, Gnai-1 / Production host: Escherichia coli (E. coli) / References: UniProt: B2RSH2
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7845.078 Da / Num. of mol.: 1 / Mutation: C68S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212
#5: Chemical ChemComp-NKP / (2R)-2-hydroxy-3-(phosphonooxy)propyl (9E)-octadec-9-enoate / 18:1 LPA / oleoyl lysophosphatidic acid


Mass: 436.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H41O7P / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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

ComponentName: complex of Lysophosphatidic Acid Receptor 1 with G-protein and LPA
Type: COMPLEX / Entity ID: #1-#4 / Source: MULTIPLE SOURCES
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Bos taurus (cattle)9913
21Rattus norvegicus (Norway rat)10116
31Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Spodoptera frugiperda (fall armyworm)7108
21Escherichia coli (E. coli)562
Buffer solutionpH: 7
SpecimenEmbedding 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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2200 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 28.2 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 31567 / Symmetry type: POINT

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