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- PDB-9yfu: Structure of GPR61 bound to inverse agonist compound 15 -

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Basic information

Entry
Database: PDB / ID: 9yfu
TitleStructure of GPR61 bound to inverse agonist compound 15
Components
  • Fab24 BAK5 heavy chain
  • Fab24 BAK5 light chain
  • G-protein coupled receptor 61,Soluble cytochrome b562
  • Hinge-binding nanobody
KeywordsSIGNALING PROTEIN / GPCR / GPR61 / orphan receptor / inverse agonist
Function / homology
Function and homology information


ligand-independent adenylate cyclase-activating G protein-coupled receptor signaling pathway / arrestin family protein binding / electron transport chain / G protein-coupled receptor activity / periplasmic space / electron transfer activity / signaling receptor complex / endosome membrane / endosome / iron ion binding ...ligand-independent adenylate cyclase-activating G protein-coupled receptor signaling pathway / arrestin family protein binding / electron transport chain / G protein-coupled receptor activity / periplasmic space / electron transfer activity / signaling receptor complex / endosome membrane / endosome / iron ion binding / G protein-coupled receptor signaling pathway / heme binding / plasma membrane
Similarity search - Function
Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / 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.
Similarity search - Domain/homology
: / Soluble cytochrome b562 / G-protein coupled receptor 61
Similarity search - Component
Biological speciesHomo sapiens (human)
Lama glama (llama)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsLees, J.A. / Dias, J.M. / Han, S.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J Med Chem / Year: 2026
Title: Discovery of Potent and Brain-Penetrant Inverse Agonists for GPR61, an Orphan G Protein-Coupled Receptor.
Authors: Ethan L Fisher / Anne-Marie Dechert Schmitt / Jamison B Tuttle / Ray Unwalla / Gabrielle H Lovett / Bethany L Kormos / Karen J Coffman / Dahui Zhou / Michael Moran / Jade Williams / Jun Xiao ...Authors: Ethan L Fisher / Anne-Marie Dechert Schmitt / Jamison B Tuttle / Ray Unwalla / Gabrielle H Lovett / Bethany L Kormos / Karen J Coffman / Dahui Zhou / Michael Moran / Jade Williams / Jun Xiao / Erik A LaChapelle / Jean-Philippe Fortin / Abdul Q Sheikh / Kimberly A Stevens / Jimmy X Kong / Emily A G Hughes / Ryan M Esquejo / Stephanie Joaquim / Nalissa L Amar / Danielle Archambault / Jeonifer Garren / Danna Breen / Srinath Jagarlapudi / Robert Dullea / Rebecca E O'Connor / Erika Koslov-Davino / Ernesto Callegari / João M Dias / Joshua A Lees / Kris Borzilleri / Seungil Han / Jonathan Brooks / Felix F Vajdos / Ashish Goyal / Lei Zhang / Yuan Zhang /
Abstract: GPR61 is a class A orphan G protein-coupled receptor (GPCR) that is predominantly expressed in the pituitary gland and appetite-regulating centers of the brain. Genome-wide association analysis, ...GPR61 is a class A orphan G protein-coupled receptor (GPCR) that is predominantly expressed in the pituitary gland and appetite-regulating centers of the brain. Genome-wide association analysis, epigenetic analysis, and animal model data have suggested that GPR61 could be a potential therapeutic target for appetite and body weight modulation. Herein, we describe our medicinal chemistry efforts in discovering a class of potent, selective, and brain-penetrant GPR61 inverse agonists. The cryogenic electron microscopy structure of GPR61 bound to compound shows that this class of inverse agonists binds to an induced, intracellular, allosteric pocket and abolishes GPR61 constitutive activity by disrupting its interactions with G protein, representing a novel mode of action of GPCR inverse agonism.
History
DepositionSep 26, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 25, 2026Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Mar 25, 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
R: G-protein coupled receptor 61,Soluble cytochrome b562
H: Fab24 BAK5 heavy chain
N: Hinge-binding nanobody
C: Fab24 BAK5 light chain
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,1795
Polymers127,7244
Non-polymers4551
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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Protein , 1 types, 1 molecules R

#1: Protein G-protein coupled receptor 61,Soluble cytochrome b562 / Biogenic amine receptor-like G-protein coupled receptor / Cytochrome b-562


Mass: 59860.707 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR61, BALGR, GPCR3, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BZJ8, UniProt: P0ABE7

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Antibody , 3 types, 3 molecules HNC

#2: Antibody Fab24 BAK5 heavy chain


Mass: 24021.787 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)
#3: Antibody Hinge-binding nanobody


Mass: 14957.326 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Lama glama (llama) / Production host: Spodoptera frugiperda (fall armyworm)
#4: Antibody Fab24 BAK5 light chain


Mass: 28884.561 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Spodoptera frugiperda (fall armyworm)

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Non-polymers , 2 types, 2 molecules

#5: Chemical ChemComp-A1CWB / N-(5-chloro-4,6-dimethylpyrimidin-2-yl)-6-{[(3,5-difluoropyridin-4-yl)methyl]amino}-2-methylpyridine-3-sulfonamide


Mass: 454.881 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17ClF2N6O2S / Feature type: SUBJECT OF INVESTIGATION
#6: 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: Complex of GPR61 ICL3 BRIL fusion with Fab24 BAK5 and Fab hinge-binding nanobody bound to inverse agonist compound 15
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277 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: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2400 nm / Nominal defocus min: 600 nm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC3.3.1particle selection
2PHENIX1.19_4092model refinement
13cryoSPARC3.3.13D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 266475 / Symmetry type: POINT
RefinementHighest resolution: 3.08 Å
Stereochemistry target values: REAL-SPACE (WEIGHTED MAP SUM AT ATOM CENTERS)
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037040
ELECTRON MICROSCOPYf_angle_d0.5739574
ELECTRON MICROSCOPYf_dihedral_angle_d4.533984
ELECTRON MICROSCOPYf_chiral_restr0.041086
ELECTRON MICROSCOPYf_plane_restr0.0061228

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