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- EMDB-67119: Cryo-EM structure of apo form of GPR75-bRIL-Fab complex -

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Basic information

Entry
Database: EMDB / ID: EMD-67119
TitleCryo-EM structure of apo form of GPR75-bRIL-Fab complex
Map data
Sample
  • Complex: Cryo-EM structure of apo form of GPR75-bRIL-Fab complex
    • Protein or peptide: Probable G-protein coupled receptor 75,Soluble cytochrome b562
    • Protein or peptide: Fab24 H
    • Protein or peptide: Fab24 L
KeywordsGPCR / GPR75 / MEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


C-C chemokine receptor activity / chemokine-mediated signaling pathway / G protein-coupled receptor activity / G protein-coupled receptor signaling pathway / plasma membrane
Similarity search - Function
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
Probable G-protein coupled receptor 75
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.91 Å
AuthorsWu C / Yuan Q
Funding support Belgium, 1 items
OrganizationGrant numberCountry
National Fund for Scientific Research Belgium
CitationJournal: Acta Pharmacol Sin / Year: 2026
Title: Cryo-EM structures of GPR75 reveal an occluded orthosteric pocket challenging conventional drug discovery paradigms for an anti-obesity target.
Authors: Zi-Ning Zhu / Chong-Zhao You / Qing-Ning Yuan / Jiu-Yin Xu / Zong-Yue Gu / Zheng Huang / Miao Liu / Bei Shan / James Jiqi Wang / Wen Hu / Kai Wang / Wan-Chao Yin / You-Wei Xu / H Eric Xu / Can-Rong Wu /
Abstract: The global obesity epidemic, affecting over 650 million adults, demands innovative therapeutics. GPR75 has emerged as a promising anti-obesity target, with genetic evidence linking loss-of-function ...The global obesity epidemic, affecting over 650 million adults, demands innovative therapeutics. GPR75 has emerged as a promising anti-obesity target, with genetic evidence linking loss-of-function variants to protection against obesity and type 2 diabetes. However, structural insights have remained elusive due to GPR75's inherent expression and stabilization challenges. Here we present the cryo-EM structures of human GPR75 in apo and Gq-coupled states, achieved through advanced stabilization techniques including NanoBiT and molecular glue approaches. Our structures reveal unique architectural features: a completely collapsed extracellular domain eliminates the traditional orthosteric binding pocket, raising critical questions about previously reported small molecule ligands. GPR75 assumes active-like conformation in both apo and G protein complexed structures through unique molecular switches-the canonical DRY motif is replaced by HRL, abolishing the ionic lock, while a distinctive Lys134-Asp210 salt bridge stabilizes the active conformation without ligand binding. This dramatic structural divergence from conventional GPCRs necessitates alternative therapeutic strategies targeting allosteric sites or protein-protein interactions rather than orthosteric pockets. Our findings establish a crucial structural framework for developing next-generation anti-obesity therapeutics.
History
DepositionNov 18, 2025-
Header (metadata) releaseFeb 4, 2026-
Map releaseFeb 4, 2026-
UpdateFeb 4, 2026-
Current statusFeb 4, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_67119.png

Downloads & links

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Map

FileDownload / File: emd_67119.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.73 Å/pix.
x 360 pix.
= 262.8 Å		0.73 Å/pix.
x 360 pix.
= 262.8 Å		0.73 Å/pix.
x 360 pix.
= 262.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.73 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.196
Minimum - Maximum-0.027608551 - 2.549481
Average (Standard dev.)0.001219759 (±0.021262547)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 262.80002 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_67119_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_67119_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of apo form of GPR75-bRIL-Fab complex

EntireName: Cryo-EM structure of apo form of GPR75-bRIL-Fab complex
Components
  • Complex: Cryo-EM structure of apo form of GPR75-bRIL-Fab complex
    • Protein or peptide: Probable G-protein coupled receptor 75,Soluble cytochrome b562
    • Protein or peptide: Fab24 H
    • Protein or peptide: Fab24 L

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Supramolecule #1: Cryo-EM structure of apo form of GPR75-bRIL-Fab complex

SupramoleculeName: Cryo-EM structure of apo form of GPR75-bRIL-Fab complex
type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Probable G-protein coupled receptor 75,Soluble cytochrome b562

MacromoleculeName: Probable G-protein coupled receptor 75,Soluble cytochrome b562
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.42302 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: ASGRQTVDEA LKDAQTSQEG NSTSLQEGLQ DLIHTATLVT CTFLLAVIFC LGSYGNFIVF LSFFDPAFRK FRTNFDFMIL NLSFCDLFI CGVTAPMFTF VLFFSSASSI PDAFCFTFHL TSSGFIIMSL KTVAVIALHR LRMVLGKQPN RTASFPCTVL L TLLLWATS ...String:
ASGRQTVDEA LKDAQTSQEG NSTSLQEGLQ DLIHTATLVT CTFLLAVIFC LGSYGNFIVF LSFFDPAFRK FRTNFDFMIL NLSFCDLFI CGVTAPMFTF VLFFSSASSI PDAFCFTFHL TSSGFIIMSL KTVAVIALHR LRMVLGKQPN RTASFPCTVL L TLLLWATS FTLATLATLK TSKSHLCLPM SSLIAGKGKA ILSLYVVDFT FCVAVVSVSY IMIAQTLRKN AERARSTLAD LE DNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDAQ KASGSGSPEM KDFRHGFDIL VGQIDDALKL ANEGKVKEAQ AAA EQLKTT RNAYIQKYLE RARSTLAKDS KAVVTCVIIV LSVLVCCLPL GISLVQVVLS SNGSFILYQF ELFGFTLIFF KSGL NPFIY SRNSAGLRRK VLWCLQS

UniProtKB: Probable G-protein coupled receptor 75, Probable G-protein coupled receptor 75

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Macromolecule #2: Fab24 H

MacromoleculeName: Fab24 H / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 11.625881 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYLYYSLVT FGQGTKVE

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Macromolecule #3: Fab24 L

MacromoleculeName: Fab24 L / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 13.207707 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
VQLVESGGGL VQPGGSLRLS CAASGFNVVV FSIHWVRQAP GKGLEWVAYI SSSSGSTSYA DSVKGRFTIS ADTSKNTAYL QMNSLRAED TAVYYCARWG YWPGEPWWKA FDYWGQGTLV TV

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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: 7.4
VitrificationCryogen name: ETHANE

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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: 18.0 µm / Nominal defocus min: 8.0 µm
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: INSILICO MODEL
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.91 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 91159
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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