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- EMDB-72906: Structure of GPR61 bound to inverse agonist compound 15 -

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Basic information

Entry
Database: EMDB / ID: EMD-72906
TitleStructure of GPR61 bound to inverse agonist compound 15
Map data
Sample
  • Complex: Complex of GPR61 ICL3 BRIL fusion with Fab24 BAK5 and Fab hinge-binding nanobody bound to inverse agonist compound 15
    • Protein or peptide: G-protein coupled receptor 61,Soluble cytochrome b562
    • Protein or peptide: Fab24 BAK5 heavy chain
    • Protein or peptide: Hinge-binding nanobody
    • Protein or peptide: Fab24 BAK5 light chain
  • Ligand: N-(5-chloro-4,6-dimethylpyrimidin-2-yl)-6-{[(3,5-difluoropyridin-4-yl)methyl]amino}-2-methylpyridine-3-sulfonamide
  • Ligand: water
KeywordsGPCR / GPR61 / orphan receptor / inverse agonist / SIGNALING PROTEIN
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.08 Å
AuthorsLees JA / Dias JM / Han S
Funding support1 items
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, 2025-
Header (metadata) releaseMar 25, 2026-
Map releaseMar 25, 2026-
UpdateMar 25, 2026-
Current statusMar 25, 2026Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_72906.png

Downloads & links

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Map

FileDownload / File: emd_72906.map.gz / Format: CCP4 / Size: 59.6 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.18 Å/pix.
x 250 pix.
= 295. Å		1.18 Å/pix.
x 250 pix.
= 295. Å		1.18 Å/pix.
x 250 pix.
= 295. Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.18 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.2
Minimum - Maximum-2.6032581 - 4.2660666
Average (Standard dev.)-0.0008546107 (±0.05677465)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions250250250
Spacing250250250
CellA=B=C: 295.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_72906_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_72906_half_map_2.map
Projections & Slices
AxesZYX

Projections

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Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Complex of GPR61 ICL3 BRIL fusion with Fab24 BAK5 and Fab hinge-b...

EntireName: Complex of GPR61 ICL3 BRIL fusion with Fab24 BAK5 and Fab hinge-binding nanobody bound to inverse agonist compound 15
Components
  • Complex: Complex of GPR61 ICL3 BRIL fusion with Fab24 BAK5 and Fab hinge-binding nanobody bound to inverse agonist compound 15
    • Protein or peptide: G-protein coupled receptor 61,Soluble cytochrome b562
    • Protein or peptide: Fab24 BAK5 heavy chain
    • Protein or peptide: Hinge-binding nanobody
    • Protein or peptide: Fab24 BAK5 light chain
  • Ligand: N-(5-chloro-4,6-dimethylpyrimidin-2-yl)-6-{[(3,5-difluoropyridin-4-yl)methyl]amino}-2-methylpyridine-3-sulfonamide
  • Ligand: water

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Supramolecule #1: Complex of GPR61 ICL3 BRIL fusion with Fab24 BAK5 and Fab hinge-b...

SupramoleculeName: Complex of GPR61 ICL3 BRIL fusion with Fab24 BAK5 and Fab hinge-binding nanobody bound to inverse agonist compound 15
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: G-protein coupled receptor 61,Soluble cytochrome b562

MacromoleculeName: G-protein coupled receptor 61,Soluble cytochrome b562 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.860707 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: YPYDVPDYAE SSPIPQSSGN SSTLGRVPQT PGPSTASGVP EVGLRDVASE SVALFFMLLL DLTAVAGNAA VMAVIAKTPA LRKFVFVFH LCLVDLLAAL TLMPLAMLSS SALFDHALFG EVACRLYLFL SVCFVSLAIL SVSAINVERY YYVVHPMRYE V RMTLGLVA ...String:
YPYDVPDYAE SSPIPQSSGN SSTLGRVPQT PGPSTASGVP EVGLRDVASE SVALFFMLLL DLTAVAGNAA VMAVIAKTPA LRKFVFVFH LCLVDLLAAL TLMPLAMLSS SALFDHALFG EVACRLYLFL SVCFVSLAIL SVSAINVERY YYVVHPMRYE V RMTLGLVA SVLVGVWVKA LAMASVPVLG RVSWEEGAPS VPPGCSLQWS HSAYCQLFVV VFAVLYFLLP LLLILVVYCS MF RARRQLA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDAQ KATPPKLEDK SPDSPEMKDF RHGFDILVGQ IDD ALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLERAR STLQKEVKAA VVLLAVGGQF LLCWLPYFSF HLYVALSAQP ISTG QVESV VTWIGYFCFT SNPFFYGCLN RQIRGELSKQ FVCFFKPAPE EELRLPSREG SIEENFLQFL QGTGCPSESW VSRPL PSPK QEPPAVDFRI PGQIAEETSE FLEQQLTSDI IMSDSYLRPA ASPRLESGSD YKDDDDAK

UniProtKB: G-protein coupled receptor 61, Soluble cytochrome b562, G-protein coupled receptor 61

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Macromolecule #2: Fab24 BAK5 heavy chain

MacromoleculeName: Fab24 BAK5 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 24.021787 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: EVQLVESGGG LVQPGGSLRL SCAASGFNVR SFSIHWVRQA PGKGLEWVAY ISSSSGSTSY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCARW GYWPGEPWWK AFDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ...String:
EVQLVESGGG LVQPGGSLRL SCAASGFNVR SFSIHWVRQA PGKGLEWVAY ISSSSGSTSY ADSVKGRFTI SADTSKNTAY LQMNSLRAE DTAVYYCARW GYWPGEPWWK AFDYWGQGTL VTVSSASTKG PSVFPLAPSS KSTSGGTAAL GCLVKDYFPE P VTVSWNSG ALTSGVHTFP AVLQSSGLYS LSSVVTVPSS SLGTQTYICN VNHKPSNTKV DKKVEPKS

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Macromolecule #3: Hinge-binding nanobody

MacromoleculeName: Hinge-binding nanobody / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 14.957326 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
HHHHHHGENL YFQGSQVQLQ ESGGGLVQPG GSLRLSCAAS GRTISRYAMS WFRQAPGKER EFVAVARRSG DGAFYADSVQ GRFTVSRDD AKTVYLQMNS LKPEDTAVYY CAIDSDTFYS GSYDYWGQGT QVTVSS

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Macromolecule #4: Fab24 BAK5 light chain

MacromoleculeName: Fab24 BAK5 light chain / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.884561 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKKNIAFLLA SMFVFSIATN AYASDIQMTQ SPSSLSASVG DRVTITCRAS QSVSSAVAWY QQKPGKAPKL LIYSASSLYS GVPSRFSGS RSGTDFTLTI SSLQPEDFAT YYCQQYLYYS LVTFGQGTKV EIKRTVAAPS VFIFPPSDSQ LKSGTASVVC L LNNFYPRE ...String:
MKKNIAFLLA SMFVFSIATN AYASDIQMTQ SPSSLSASVG DRVTITCRAS QSVSSAVAWY QQKPGKAPKL LIYSASSLYS GVPSRFSGS RSGTDFTLTI SSLQPEDFAT YYCQQYLYYS LVTFGQGTKV EIKRTVAAPS VFIFPPSDSQ LKSGTASVVC L LNNFYPRE AKVQWKVDNA LQSGNSQESV TEQDSKDSTY SLSSTLTLSK ADYEKHKVYA CEVTHQGLSS PVTKSFNRGE MK KNIAFLL ASMFVFSIAT NAYAEIS

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Macromolecule #5: N-(5-chloro-4,6-dimethylpyrimidin-2-yl)-6-{[(3,5-difluoropyridin-...

MacromoleculeName: N-(5-chloro-4,6-dimethylpyrimidin-2-yl)-6-{[(3,5-difluoropyridin-4-yl)methyl]amino}-2-methylpyridine-3-sulfonamide
type: ligand / ID: 5 / Number of copies: 1 / Formula: A1CWB
Molecular weightTheoretical: 454.881 Da

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Macromolecule #6: water

MacromoleculeName: water / type: ligand / ID: 6 / Number of copies: 1 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: GOLD / Mesh: 200 / Support film - Material: CARBON / Support film - topology: HOLEY ARRAY / Pretreatment - Type: GLOW DISCHARGE / Pretreatment - Time: 30 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.4 µm / Nominal defocus min: 0.6 µm
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.08 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 3.3.1) / Number images used: 266475
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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