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Yorodumi- PDB-8iyx: Cryo-EM structure of the GPR34 receptor in complex with the antag... -
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-Basic information
Entry | Database: PDB / ID: 8iyx | ||||||||||||
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Title | Cryo-EM structure of the GPR34 receptor in complex with the antagonist YL-365 | ||||||||||||
Components | Probable G-protein coupled receptor 34,YL-365 | ||||||||||||
Keywords | MEMBRANE 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 | ||||||||||||
Biological species | Homo sapiens (human) | ||||||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.34 Å | ||||||||||||
Authors | Jia, G.W. / Wang, X. / Zhang, C.B. / Dong, H.H. / Su, Z.M. | ||||||||||||
Funding support | China, 3items
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Citation | Journal: 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 |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8iyx.cif.gz | 68.5 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8iyx.ent.gz | 44.9 KB | Display | PDB format |
PDBx/mmJSON format | 8iyx.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8iyx_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8iyx_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8iyx_validation.xml.gz | 26.1 KB | Display | |
Data in CIF | 8iyx_validation.cif.gz | 35.6 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/iy/8iyx ftp://data.pdbj.org/pub/pdb/validation_reports/iy/8iyx | HTTPS FTP |
-Related structure data
Related structure data | 35832MC 8saiC M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | 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 |
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#2: Chemical | ChemComp-S6R / Mass: 583.073 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H31ClN2O5 / Feature type: SUBJECT OF INVESTIGATION |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Cryo-EM structure of the GPR34 receptor in complex with the antagonist YL-365 Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Spodoptera frugiperda (fall armyworm) |
Buffer solution | pH: 7.5 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 700 nm |
Image recording | Electron dose: 56.7 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.19_4092: / Classification: refinement | ||||||||||||||||||||||||
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CTF correction | Type: NONE | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.34 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 3266074 / Symmetry type: POINT | ||||||||||||||||||||||||
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