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Basic information

Entry
Database: PDB / ID: 9m42
TitleStructure-based discovery of potent agonists of the orphan receptor GPR139
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Endo-1,4-beta-xylanase,Probable G-protein coupled receptor 139
  • Nanobody 35
KeywordsSTRUCTURAL PROTEIN / GPR139 / Complex / G protein
Function / homology
Function and homology information


neuropeptide receptor activity / endo-1,4-beta-xylanase activity / endo-1,4-beta-xylanase / xylan catabolic process / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress ...neuropeptide receptor activity / endo-1,4-beta-xylanase activity / endo-1,4-beta-xylanase / xylan catabolic process / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / regulation of insulin secretion / cellular response to glucagon stimulus / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / bone development / platelet aggregation / cognition / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / adenylate cyclase-activating G protein-coupled receptor 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / 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 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / 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 / Inactivation, recovery and regulation of the phototransduction cascade / G alpha (12/13) signalling events / extracellular vesicle / sensory perception of taste / positive regulation of cold-induced thermogenesis / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / G protein activity / retina development in camera-type eye / GTPase binding / 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 / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / GTP binding / protein-containing complex binding / signal transduction / extracellular exosome / metal ion binding / identical protein binding / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
G-protein-coupled receptor GPR139 / : / Glycoside hydrolase family 11, active site 2 / Glycosyl hydrolases family 11 (GH11) active site signature 2. / Glycoside hydrolase family 11, active site 1 / Glycosyl hydrolases family 11 (GH11) active site signature 1. / Glycoside hydrolase family 11 / Glycosyl hydrolases family 11 (GH11) domain / Glycosyl hydrolases family 11 / Glycosyl hydrolases family 11 (GH11) domain profile. ...G-protein-coupled receptor GPR139 / : / Glycoside hydrolase family 11, active site 2 / Glycosyl hydrolases family 11 (GH11) active site signature 2. / Glycoside hydrolase family 11, active site 1 / Glycosyl hydrolases family 11 (GH11) active site signature 1. / Glycoside hydrolase family 11 / Glycosyl hydrolases family 11 (GH11) domain / Glycosyl hydrolases family 11 / Glycosyl hydrolases family 11 (GH11) domain profile. / Glycoside hydrolase family 11/12 / G-protein alpha subunit, group S / 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 / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / Concanavalin A-like lectin/glucanase domain superfamily / 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
: / Endo-1,4-beta-xylanase / 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 / Probable G-protein coupled receptor 139
Similarity search - Component
Biological speciesHomo sapiens (human)
Niallia circulans (bacteria)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsCabezadevaca, I. / Trapkov, B. / Shen, L. / Pezeshki, M. / Zhang, X.H. / Liu, Z.j. / Hauser, A.S. / Carlsson, J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Nat Commun / Year: 2025
Title: Ultra-large virtual screening unveils potent agonists of the neuromodulatory orphan receptor GPR139.
Authors: Israel Cabeza de Vaca / Boris Trapkov / Ling Shen / Duy Duc Vo / Xiaoqun Zhang / Yunting Yang / Mitra Pezeshki / Xuehan Zhang / Frida Bällgren / Aljona Saleh / Andrii V Tarnovskiy / Dmytro ...Authors: Israel Cabeza de Vaca / Boris Trapkov / Ling Shen / Duy Duc Vo / Xiaoqun Zhang / Yunting Yang / Mitra Pezeshki / Xuehan Zhang / Frida Bällgren / Aljona Saleh / Andrii V Tarnovskiy / Dmytro S Radchenko / Yurii S Moroz / Hans Bräuner-Osborne / Per Svenningsson / Jan Kihlberg / Zhi-Jie Liu / Alexander Sebastian Hauser / Jens Carlsson /
Abstract: The orphan G protein-coupled receptor (GPCR) GPR139 attracts interest as a target for neuropsychiatric disorders. Whereas the physiological functions of GPR139 remain elusive, a high-resolution ...The orphan G protein-coupled receptor (GPCR) GPR139 attracts interest as a target for neuropsychiatric disorders. Whereas the physiological functions of GPR139 remain elusive, a high-resolution receptor structure is now available. To assess whether structural information enables ligand discovery, we computationally dock 235 million compounds to the GPR139 binding site. Of 68 top-ranked compounds evaluated experimentally, five are full agonists with potencies ranging from 160 nM to 3.6 µM. Structure-guided optimization identifies one of the most potent GPR139 agonists, and a cryo-EM structure of the receptor-ligand complex confirms the predicted binding mode. Functional characterization provides insights into GPR139 signalling, and one agonist elicits behavioural effects in mice. We also explore the potential to replace experimental structure determination with the deep-learning method AlphaFold3, revealing a limited capability of artificial intelligence to model receptor-ligand interactions for understudied GPCRs. The results demonstrate how high-resolution GPCR structures combined with large-library docking can accelerate drug discovery.
History
DepositionMar 3, 2025Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jan 21, 2026Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Jan 21, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
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
N: Nanobody 35
R: Endo-1,4-beta-xylanase,Probable G-protein coupled receptor 139
hetero molecules


Theoretical massNumber of molelcules
Total (without water)157,4336
Polymers157,1065
Non-polymers3271
Water181
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 ABG

#1: Protein Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-stimulating G alpha protein


Mass: 30595.510 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAS, GNAS1, GSP / Production host: Escherichia coli (E. coli)
References: UniProt: P63092, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37564.102 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 10497.960 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

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Antibody / Protein , 2 types, 2 molecules NR

#4: Antibody Nanobody 35


Mass: 17483.693 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Escherichia coli (E. coli)
#5: Protein Endo-1,4-beta-xylanase,Probable G-protein coupled receptor 139 / Xylanase / 1 / 4-beta-D-xylan xylanohydrolase / G(q)-coupled orphan receptor GPRg1 / G-protein- ...Xylanase / 1 / 4-beta-D-xylan xylanohydrolase / G(q)-coupled orphan receptor GPRg1 / G-protein-coupled receptor PGR3


Mass: 60964.281 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: Chimera of Endo-1,4-beta-xylanase and Probable G-protein coupled receptor 139
Source: (gene. exp.) Niallia circulans (bacteria), (gene. exp.) Homo sapiens (human)
Gene: xlnA, GPR139, GPRG1, PGR3 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P09850, UniProt: Q6DWJ6, endo-1,4-beta-xylanase

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Non-polymers , 2 types, 2 molecules

#6: Chemical ChemComp-A1L8O / 2-[5-(4-methylthiophen-3-yl)-1,2,4-oxadiazol-3-yl]-~{N}-[(1~{S})-1-phenylethyl]ethanamide


Mass: 327.401 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H17N3O2S / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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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: GPR139_Gs/q / Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Escherichia coli (E. coli)562
21Spodoptera frugiperda (fall armyworm)7108
Buffer solutionpH: 7.5
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: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2000 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2PHENIX1.20.1_4487model refinement
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 138265 / Symmetry type: POINT
RefinementHighest resolution: 3.2 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0038484
ELECTRON MICROSCOPYf_angle_d0.63211506
ELECTRON MICROSCOPYf_dihedral_angle_d4.671145
ELECTRON MICROSCOPYf_chiral_restr0.0431299
ELECTRON MICROSCOPYf_plane_restr0.0041459

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