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- PDB-9qxl: The structure of ADGRL4 in the active-state -

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Basic information

Entry
Database: PDB / ID: 9qxl
TitleThe structure of ADGRL4 in the active-state
Components
  • GNAS complex locus,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
  • Green fluorescent protein,Adhesion G protein-coupled receptor L4
  • 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
KeywordsMEMBRANE PROTEIN / Adhesion GPCR / ADGRL4 / ELTD1
Function / homology
Function and homology information


PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / intracellular transport / D1 dopamine receptor binding / vascular endothelial cell response to laminar fluid shear stress / activation of adenylate cyclase activity / renal water homeostasis / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway ...PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / intracellular transport / D1 dopamine receptor binding / vascular endothelial cell response to laminar fluid shear stress / activation of adenylate cyclase activity / renal water homeostasis / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of insulin secretion / cellular response to glucagon stimulus / bioluminescence / adenylate cyclase activator activity / trans-Golgi network membrane / generation of precursor metabolites and energy / negative regulation of inflammatory response to antigenic stimulus / bone development / G protein-coupled receptor activity / platelet aggregation / cognition / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Glucagon-type ligand receptors / Sensory perception of sweet, bitter, and umami (glutamate) taste / Adrenaline,noradrenaline inhibits insulin secretion / sensory perception of smell / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / G-protein beta-subunit binding / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / positive regulation of cold-induced thermogenesis / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / retina development in camera-type eye / G protein activity / GTPase binding / cytoplasmic vesicle / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / cell surface receptor signaling pathway / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / calcium ion binding / synapse / GTP binding / protein-containing complex binding / signal transduction / extracellular exosome / metal ion binding / membrane / plasma membrane / cytoplasm / cytosol
Similarity search - Function
GAIN domain, N-terminal / AGRL2-4 GAIN subdomain A / GPCR proteolysis site, GPS, motif / GAIN domain superfamily / : / GPS motif / G-protein-coupled receptor proteolytic site domain / GAIN-B domain profile. / : / Calcium-binding EGF domain ...GAIN domain, N-terminal / AGRL2-4 GAIN subdomain A / GPCR proteolysis site, GPS, motif / GAIN domain superfamily / : / GPS motif / G-protein-coupled receptor proteolytic site domain / GAIN-B domain profile. / : / Calcium-binding EGF domain / G-protein coupled receptors family 2 signature 2. / GPCR, family 2, secretin-like, conserved site / GPCR, family 2, secretin-like / 7 transmembrane receptor (Secretin family) / GPCR, family 2-like / G-protein coupled receptors family 2 profile 2. / G-protein alpha subunit, group S / EGF-type aspartate/asparagine hydroxylation site / EGF-like calcium-binding, conserved site / Calcium-binding EGF-like domain signature. / Aspartic acid and asparagine hydroxylation site. / EGF-like calcium-binding domain / Calcium-binding EGF-like domain / Epidermal growth factor-like domain. / Green fluorescent protein, GFP / Green fluorescent protein-related / Green fluorescent protein / Green fluorescent protein / EGF-like domain profile. / EGF-like domain signature 2. / EGF-like domain / 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 / EF-hand calcium-binding domain. / 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 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
Green fluorescent protein / 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(s) subunit alpha isoforms short / GNAS complex locus / Adhesion G protein-coupled receptor L4
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.14 Å
AuthorsChen, Q. / Favara, D.M.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Cancer Research UKRCCPOB-May22 - 100008 United Kingdom
CitationJournal: Nat Commun / Year: 2025
Title: Structure of the G-coupled adhesion receptor ADGRL4.
Authors: Qingchao Chen / Anastasiia Gusach / Aurora Diamante / Jayesh C Patel / Patricia C Edwards / Christopher G Tate / David M Favara /
Abstract: Adhesion G protein-coupled receptors (aGPCRs) are a 32-member family of Class B GPCRs that have diverse cellular roles including mechanosensation, cell-fate determination, neurodevelopment, immune ...Adhesion G protein-coupled receptors (aGPCRs) are a 32-member family of Class B GPCRs that have diverse cellular roles including mechanosensation, cell-fate determination, neurodevelopment, immune function and tumour biology. ADGRL4 is upregulated in the tumour microenvironment and is implicated in tumour pathogenesis across a broad range of malignancies. Inhibiting ADGRL4 is a potential therapeutic treatment for currently intractable cancers such as glioblastoma. Previous work suggested that ADGRL4 does not signal through G protein coupled pathways. However, using a sensitive bioluminescent assay, we demonstrate here that ADGRL4 couples weakly to the heterotrimeric G protein G, whilst there is no robust coupling to other G proteins (G, G, G) or β-arrestin 1 or 2. We determine the cryo-EM structure of ADGRL4 coupled to a heterotrimeric G complex to a resolution of 3.1 Å. The overall fold of ADGRL4 is similar to that of other aGPCRs, but the coupling to G is distinct with fewer interactions between the receptor and G protein. The structure is consistent with ADGRL4 being activated by its tethered agonist and represents an important step towards the development of potential inhibitors for the treatment of multiple tumour types.
History
DepositionApr 15, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 14, 2026Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Green fluorescent protein,Adhesion G protein-coupled receptor L4
B: GNAS complex locus,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
C: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
E: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2


Theoretical massNumber of molelcules
Total (without water)146,9774
Polymers146,9774
Non-polymers00
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

#1: Protein Green fluorescent protein,Adhesion G protein-coupled receptor L4 / EGF / latrophilin and seven transmembrane domain-containing protein 1 / EGF-TM7-latrophilin-related ...EGF / latrophilin and seven transmembrane domain-containing protein 1 / EGF-TM7-latrophilin-related protein / ETL protein


Mass: 70008.250 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GFP, ADGRL4, ELTD1, ETL, UNQ202/PRO228 / Production host: Homo sapiens (human) / References: UniProt: P42212, UniProt: Q9HBW9
#2: Protein GNAS complex locus,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 30585.227 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS, GNAS1, GSP / Production host: Homo sapiens (human)
References: UniProt: Q5JWD1, UniProt: P63092, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 38522.098 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768
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
1ADGRL4 complexCOMPLEXall0RECOMBINANT
2Adhesion G protein-coupled receptor L4COMPLEX#11RECOMBINANT
3mini-GqCOMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#31RECOMBINANT
5G-subunit gamma-2COMPLEX#41RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.096 MDaNO
210.032 MDaNO
310.029 MDaNO
410.037 MDaNO
510.0079 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
65Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Trichoplusia ni (cabbage looper)7111
65Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.4
SpecimenConc.: 1.1 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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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: SPOT SCAN
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1800 nm / Nominal defocus min: 800 nm / Cs: 2.7 mm / C2 aperture diameter: 100 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 60 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.21_5207:model refinement
5cryoSPARCCTF correction
12cryoSPARCclassification
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.14 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 339728 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0047097
ELECTRON MICROSCOPYf_angle_d0.8119613
ELECTRON MICROSCOPYf_dihedral_angle_d4.667956
ELECTRON MICROSCOPYf_chiral_restr0.0531081
ELECTRON MICROSCOPYf_plane_restr0.0071221

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