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- PDB-8iyx: Cryo-EM structure of the GPR34 receptor in complex with the antag... -

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Entry
Database: PDB / ID: 8iyx
TitleCryo-EM structure of the GPR34 receptor in complex with the antagonist YL-365
ComponentsProbable G-protein coupled receptor 34,YL-365
KeywordsMEMBRANE PROTEIN/INHIBITOR / Inhibitor / GPR34 receptor in complex with the antagonist YL-365 / MEMBRANE PROTEIN / MEMBRANE PROTEIN-INHIBITOR complex
Function / homology
Function and homology information


G protein-coupled purinergic nucleotide receptor activity / G protein-coupled receptor activity / G protein-coupled receptor signaling pathway / plasma membrane
Similarity search - Function
: / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family)
Similarity search - Domain/homology
: / Probable G-protein coupled receptor 34
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsJia, G.W. / Wang, X. / Zhang, C.B. / Dong, H.H. / Su, Z.M.
Funding support China, 3items
OrganizationGrant numberCountry
Ministry of Science and Technology (MoST, China)2022YFC2303700 China
Ministry of Science and Technology (MoST, China)2021YFA1301900 China
National Natural Science Foundation of China (NSFC)NSFC 32222040 China
CitationJournal: Proc Natl Acad Sci U S A / Year: 2023
Title: Cryo-EM structures of human GPR34 enable the identification of selective antagonists.
Authors: Anjie Xia / Xihao Yong / Changbin Zhang / Guifeng Lin / Guowen Jia / Chang Zhao / Xin Wang / Yize Hao / Yifei Wang / Pei Zhou / Xin Yang / Yue Deng / Chao Wu / Yujiao Chen / Jiawei Zhu / ...Authors: Anjie Xia / Xihao Yong / Changbin Zhang / Guifeng Lin / Guowen Jia / Chang Zhao / Xin Wang / Yize Hao / Yifei Wang / Pei Zhou / Xin Yang / Yue Deng / Chao Wu / Yujiao Chen / Jiawei Zhu / Xiaodi Tang / Jingming Liu / Shiyu Zhang / Jiahao Zhang / Zheng Xu / Qian Hu / Jinlong Zhao / Yuting Yue / Wei Yan / Zhaoming Su / Yuquan Wei / Rongbin Zhou / Haohao Dong / Zhenhua Shao / Shengyong Yang /
Abstract: GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron ...GPR34 is a functional G-protein-coupled receptor of Lysophosphatidylserine (LysoPS), and has pathogenic roles in numerous diseases, yet remains poorly targeted. We herein report a cryo-electron microscopy (cryo-EM) structure of GPR34 bound with LysoPS (18:1) and G protein, revealing a unique ligand recognition mode with the negatively charged head group of LysoPS occupying a polar cavity formed by TM3, 6 and 7, and the hydrophobic tail of LysoPS residing in a lateral open hydrophobic groove formed by TM3-5. Virtual screening and subsequent structural optimization led to the identification of a highly potent and selective antagonist (YL-365). Design of fusion proteins allowed successful determination of the challenging cryo-EM structure of the inactive GPR34 complexed with YL-365, which revealed the competitive binding of YL-365 in a portion of the orthosteric binding pocket of GPR34 and the antagonist-binding-induced allostery in the receptor, implicating the inhibition mechanism of YL-365. Moreover, YL-365 displayed excellent activity in a neuropathic pain model without obvious toxicity. Collectively, this study offers mechanistic insights into the endogenous agonist recognition and antagonist inhibition of GPR34, and provides proof of concept that targeting GPR34 represents a promising strategy for disease treatment.
History
DepositionApr 6, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Mar 20, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
C: Probable G-protein coupled receptor 34,YL-365
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,8152
Polymers66,2321
Non-polymers5831
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein Probable G-protein coupled receptor 34,YL-365


Mass: 66231.812 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GPR34 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9UPC5
#2: Chemical ChemComp-S6R / 1-[4-(3-chlorophenyl)phenyl]carbonyl-4-[2-(4-phenylmethoxyphenyl)ethanoylamino]piperidine-4-carboxylic acid


Mass: 583.073 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H31ClN2O5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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 the GPR34 receptor in complex with the antagonist YL-365
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
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
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2500 nm / Nominal defocus min: 700 nm
Image recordingElectron dose: 56.7 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19_4092: / Classification: refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3266074 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0032260
ELECTRON MICROSCOPYf_angle_d0.5883058
ELECTRON MICROSCOPYf_dihedral_angle_d4.89296
ELECTRON MICROSCOPYf_chiral_restr0.038363
ELECTRON MICROSCOPYf_plane_restr0.004353

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