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- EMDB-35832: Cryo-EM structure of the GPR34 receptor in complex with the antag... -

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Basic information

Entry
Database: EMDB / ID: EMD-35832
TitleCryo-EM structure of the GPR34 receptor in complex with the antagonist YL-365
Map data
Sample
  • Complex: Cryo-EM structure of the GPR34 receptor in complex with the antagonist YL-365
    • Protein or peptide: Probable G-protein coupled receptor 34,Probable G-protein coupled receptor 34,YL-365
  • Ligand: 1-[4-(3-chlorophenyl)phenyl]carbonyl-4-[2-(4-phenylmethoxyphenyl)ethanoylamino]piperidine-4-carboxylic acid
KeywordsInhibitor / 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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.34 Å
AuthorsJia GW / Wang X / Zhang CB / Dong HH / Su ZM
Funding support China, 3 items
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, 2023-
Header (metadata) releaseMar 20, 2024-
Map releaseMar 20, 2024-
UpdateOct 23, 2024-
Current statusOct 23, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_35832.png

Downloads & links

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Map

FileDownload / File: emd_35832.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

Projections

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.23
Minimum - Maximum-0.6553645 - 1.3071167
Average (Standard dev.)0.0008850846 (±0.026590332)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_35832_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_35832_half_map_2.map
Projections & Slices
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Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of the GPR34 receptor in complex with the antag...

EntireName: Cryo-EM structure of the GPR34 receptor in complex with the antagonist YL-365
Components
  • Complex: Cryo-EM structure of the GPR34 receptor in complex with the antagonist YL-365
    • Protein or peptide: Probable G-protein coupled receptor 34,Probable G-protein coupled receptor 34,YL-365
  • Ligand: 1-[4-(3-chlorophenyl)phenyl]carbonyl-4-[2-(4-phenylmethoxyphenyl)ethanoylamino]piperidine-4-carboxylic acid

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Supramolecule #1: Cryo-EM structure of the GPR34 receptor in complex with the antag...

SupramoleculeName: Cryo-EM structure of the GPR34 receptor in complex with the antagonist YL-365
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Probable G-protein coupled receptor 34,Probable G-protein coupled...

MacromoleculeName: Probable G-protein coupled receptor 34,Probable G-protein coupled receptor 34,YL-365
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 66.231812 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MRSHTITMTT TSVSSWPYSS HRMRFITNHS DQPPQNFSAT PNVTTCPMDE KLLSTVLTTS YSVIFIVGLV GNIIALYVFL GIHRKRNSI QIYLLNVAIA DLLLIFCLPF RIMYHINQNK WTLGVILCKV VGTLFYMNMY ISIILLGFIS LDRYIKINRS I QQRKAITT ...String:
MRSHTITMTT TSVSSWPYSS HRMRFITNHS DQPPQNFSAT PNVTTCPMDE KLLSTVLTTS YSVIFIVGLV GNIIALYVFL GIHRKRNSI QIYLLNVAIA DLLLIFCLPF RIMYHINQNK WTLGVILCKV VGTLFYMNMY ISIILLGFIS LDRYIKINRS I QQRKAITT KQSIYVCCIV WMLALGGFLT MIILTLKKGG HNSTMCFHYR DKHNAKGEAI FNFILVVMFW LIFLLIILSY IK IGKNLLR ISKRGIDCSF WNESYLTGSR DERKKSLLSK FGMDEGVTFM FIGRFDRGQK GVDVLLKAIE ILSSKKEFQE MRF IIIGKG DPELEGWARS LEEKHGNVKV ITEMLSREFV RELYGSVDFV IIPSYFEPFG LVALEAMCLG AIPIASAVGG LRDI ITNET GILVKAGDPG ELANAILKAL ELSRSDLSKF RENCKKRAMS FSDQARMDIR LAKGKYATTA RNSFIVLIIF TICFV PYHA FRFIYISSQL NVSSCYWKEI VHKTNEIMLV LSSFNSCLDP VMYFLMSSNI RKIMCQLLFR RFQGEPSRSE STSEFK PGY SLHDTSVAVK IQSSSKST

UniProtKB: Probable G-protein coupled receptor 34, Probable G-protein coupled receptor 34

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Macromolecule #2: 1-[4-(3-chlorophenyl)phenyl]carbonyl-4-[2-(4-phenylmethoxyphenyl)...

MacromoleculeName: 1-[4-(3-chlorophenyl)phenyl]carbonyl-4-[2-(4-phenylmethoxyphenyl)ethanoylamino]piperidine-4-carboxylic acid
type: ligand / ID: 2 / Number of copies: 1 / Formula: S6R
Molecular weightTheoretical: 583.073 Da

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 QUANTUM (4k x 4k) / Average electron dose: 56.7 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.7000000000000001 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 3266074
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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