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- EMDB-67108: Cryo-EM structure of Receptor of GPR75 -

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Basic information

Entry
Database: EMDB / ID: EMD-67108
TitleCryo-EM structure of Receptor of GPR75
Map data
Sample
  • Complex: The cryo_EM structure of GPR75 complex
KeywordsGPCR / GPR75 / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.5 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_67108.png

Downloads & links

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Map

FileDownload / File: emd_67108.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.82 Å/pix.
x 320 pix.
= 263.68 Å		0.82 Å/pix.
x 320 pix.
= 263.68 Å		0.82 Å/pix.
x 320 pix.
= 263.68 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.824 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.387
Minimum - Maximum-2.446853 - 4.4045672
Average (Standard dev.)-0.0014802429 (±0.04145498)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 263.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_67108_half_map_1.map
Projections & Slices
AxesZYX

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Half map: #2

Fileemd_67108_half_map_2.map
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Sample components

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Entire : The cryo_EM structure of GPR75 complex

EntireName: The cryo_EM structure of GPR75 complex
Components
  • Complex: The cryo_EM structure of GPR75 complex

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Supramolecule #1: The cryo_EM structure of GPR75 complex

SupramoleculeName: The cryo_EM structure of GPR75 complex / type: complex / ID: 1 / Parent: 0
Source (natural)Organism: Homo sapiens (human)

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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: 3.5 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC / Number images used: 165458
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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