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- PDB-9xqn: Cryo-EM structure of apo form of GPR75-bRIL-Fab complex -

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Basic information

Entry
Database: PDB / ID: 9xqn
TitleCryo-EM structure of apo form of GPR75-bRIL-Fab complex
Components
  • Fab24 H
  • Fab24 L
  • Probable G-protein coupled receptor 75,Soluble cytochrome b562
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / GPCR / GPR75 / 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)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.91 Å
AuthorsWu, C. / Yuan, Q.
Funding support Belgium, 1items
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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Feb 4, 2026Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Feb 4, 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

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Assembly

Deposited unit
A: Probable G-protein coupled receptor 75,Soluble cytochrome b562
B: Fab24 H
C: Fab24 L


Theoretical massNumber of molelcules
Total (without water)71,2573
Polymers71,2573
Non-polymers00
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

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


Mass: 46423.020 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) Escherichia coli (E. coli)
Gene: GPR75, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O95800
#2: Antibody Fab24 H


Mass: 11625.881 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 Fab24 L


Mass: 13207.707 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)
Has protein modificationN

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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: Cryo-EM structure of apo form of GPR75-bRIL-Fab complex
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
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: 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: 18000 nm / Nominal defocus min: 8000 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k)

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Processing

EM software
IDNameCategory
1cryoSPARCparticle selection
13cryoSPARC3D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.91 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 91159 / Symmetry type: POINT

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