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- PDB-20zx: Cryo-EM structure of Gq-coupled LPAR5 in complex with LPA -

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Basic information

Entry
Database: PDB / ID: 20zx
TitleCryo-EM structure of Gq-coupled LPAR5 in complex with LPA
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Lysophosphatidic acid receptor 5
  • scFv16
KeywordsMEMBRANE PROTEIN / LPAR5 / LPA
Function / homology
Function and homology information


Lysosphingolipid and LPA receptors / 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 ...Lysosphingolipid and LPA receptors / 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 / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / 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) / 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 / G alpha (z) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Extra-nuclear estrogen signaling / G alpha (q) signalling events / G alpha (s) signalling events / photoreceptor outer segment membrane / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (i) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / sensory perception of taste / alkylglycerophosphoethanolamine phosphodiesterase activity / retina development in camera-type eye / behavioral response to pain / photoreceptor outer segment / cardiac muscle cell apoptotic process / photoreceptor inner segment / cell population proliferation / G protein-coupled receptor activity / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G-protein beta-subunit binding / positive regulation of cytosolic calcium ion concentration / signaling receptor complex adaptor activity / cell body / GTPase binding / cellular response to hypoxia / G alpha (i) signalling events / G alpha (q) signalling events / G protein-coupled receptor signaling pathway / GTPase activity / synapse / dendrite / protein-containing complex binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
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, 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. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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
Similarity search - Domain/homology
Chem-UBL / 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 5
Similarity search - Component
Biological speciesRattus norvegicus (Norway rat)
Bos taurus (domestic cattle)
Homo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.96 Å
AuthorsZhao, L. / Li, X.
Funding support China, 2items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32371255 China
National Natural Science Foundation of China (NSFC)32130022 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2026
Title: Structural basis for lysophosphatidic acid recognition and atypical Gα coupling by LPAR5.
Authors: Xin Li / Kai Wang / Zhongliang Xing / Min Zhang / Wen Hu / Qingning Yuan / H Eric Xu / Li-Hua Zhao /
Abstract: Lysophosphatidic acid receptor 5 (LPAR5) is a non-endothelial differentiation gene class A G protein-coupled receptor that regulates neuropathic pain, itch, and cancer progression through coupling to ...Lysophosphatidic acid receptor 5 (LPAR5) is a non-endothelial differentiation gene class A G protein-coupled receptor that regulates neuropathic pain, itch, and cancer progression through coupling to G proteins. Here, we report the cryo-EM structure of LPAR5 bound to 1-oleoyl-lysophosphatidic acid (LPA) in complex with G at 2.96 Å resolution, revealing a distinct mode of receptor activation and G protein coupling. The phosphate headgroup of LPA forms extensive polar interactions with residues from extracellular loop 2 and transmembrane helices TM5-TM7, while the lipid tail inserts into a deep hydrophobic cavity formed by TM3-TM5. Site-directed mutagenesis confirms the functional importance of these interactions. Remarkably, LPAR5 exhibits a noncanonical G protein coupling mode. Unlike previously reported GPCR-G protein structures in which the Gα C-terminal α5 helix ("wavy hook") primarily engages TM6, the wavy hook in LPAR5 is positioned toward the intracellular loop 1-helix 8 interface. This configuration is associated with limited TM6 outward displacement and modest rearrangement at the toggle-switch position (6.48). The resulting interface is stabilized by receptor-specific interactions and supported by functional data. Together, these findings reveal an alternative mode of GPCR-G protein coupling and highlight the structural plasticity underlying signaling specificity in LPA receptors.
History
DepositionDec 4, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Jun 17, 2026Provider: repository / Type: Initial release
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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
R: Lysophosphatidic acid receptor 5
A: Guanine nucleotide-binding protein G(324) subunit alpha
E: scFv16
hetero molecules


Theoretical massNumber of molelcules
Total (without water)157,7766
Polymers157,3395
Non-polymers4371
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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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: 40226.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7729.947 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63212
#4: Protein Guanine nucleotide-binding protein G(324) subunit alpha


Mass: 41708.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)

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

#3: Protein Lysophosphatidic acid receptor 5 / LPA receptor 5 / LPA-5 / G-protein coupled receptor 92 / G-protein coupled receptor 93


Mass: 41396.574 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LPAR5, GPR92, GPR93 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q9H1C0
#5: Antibody scFv16


Mass: 26277.299 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)
#6: Chemical ChemComp-UBL / [(2R)-2-oxidanyl-3-phosphonooxy-propyl] (Z)-octadec-9-enoate


Mass: 436.520 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H41O7P / 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

ComponentName: Cryo-EM structure of Gq-coupled LPAR5 in complex with LPA
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
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: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 18000 nm / Nominal defocus min: 8000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
2PHENIXmodel refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.96 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 102163 / Symmetry type: POINT
RefinementHighest resolution: 2.96 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0039268
ELECTRON MICROSCOPYf_angle_d0.49612559
ELECTRON MICROSCOPYf_dihedral_angle_d5.0161298
ELECTRON MICROSCOPYf_chiral_restr0.0391413
ELECTRON MICROSCOPYf_plane_restr0.0041601

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