+Open data
-Basic information
Entry | Database: PDB / ID: 8hvi | |||||||||
---|---|---|---|---|---|---|---|---|---|---|
Title | Activation mechanism of GPR132 by compound NOX-6-7 | |||||||||
Components |
| |||||||||
Keywords | MEMBRANE PROTEIN / GPCR / GPR132 | |||||||||
Function / homology | Function and homology information negative regulation of G2/M transition of mitotic cell cycle / Class A/1 (Rhodopsin-like receptors) / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway ...negative regulation of G2/M transition of mitotic cell cycle / Class A/1 (Rhodopsin-like receptors) / Adenylate cyclase inhibitory pathway / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G protein-coupled receptor activity / electron transport chain / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / response to peptide hormone / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / G1/S transition of mitotic cell cycle / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / periplasmic space / electron transfer activity / iron ion binding / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / heme binding / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane / cytosol / cytoplasm Similarity search - Function | |||||||||
Biological species | Escherichia coli (E. coli) Homo sapiens (human) Mus musculus (house mouse) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.04 Å | |||||||||
Authors | Wang, J.L. / Ding, J.H. / Sun, J.P. / Yu, X. | |||||||||
Funding support | China, 2items
| |||||||||
Citation | Journal: Nat Metab / Year: 2023 Title: Functional screening and rational design of compounds targeting GPR132 to treat diabetes. Authors: Jia-Le Wang / Xiao-Dong Dou / Jie Cheng / Ming-Xin Gao / Guo-Feng Xu / Wei Ding / Jin-Hui Ding / Yu Li / Si-Han Wang / Zhao-Wei Ji / Xin-Yi Zhao / Tong-Yu Huo / Cai-Fang Zhang / Ya-Meng Liu ...Authors: Jia-Le Wang / Xiao-Dong Dou / Jie Cheng / Ming-Xin Gao / Guo-Feng Xu / Wei Ding / Jin-Hui Ding / Yu Li / Si-Han Wang / Zhao-Wei Ji / Xin-Yi Zhao / Tong-Yu Huo / Cai-Fang Zhang / Ya-Meng Liu / Xue-Ying Sha / Jia-Rui Gao / Wen-Hui Zhang / Yong Hao / Cheng Zhang / Jin-Peng Sun / Ning Jiao / Xiao Yu / Abstract: Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling ...Chronic inflammation due to islet-residing macrophages plays key roles in the development of type 2 diabetes mellitus. By systematically profiling intra-islet lipid-transmembrane receptor signalling in islet-resident macrophages, we identified endogenous 9(S)-hydroxy-10,12-octadecadienoic acid-G-protein-coupled receptor 132 (GPR132)-Gi signalling as a significant contributor to islet macrophage reprogramming and found that GPR132 deficiency in macrophages reversed metabolic disorders in mice fed a high-fat diet. The cryo-electron microscopy structures of GPR132 bound with two endogenous agonists, N-palmitoylglycine and 9(S)-hydroxy-10,12-octadecadienoic acid, enabled us to rationally design both GPR132 agonists and antagonists with high potency and selectivity through stepwise translational approaches. We ultimately identified a selective GPR132 antagonist, NOX-6-18, that modulates macrophage reprogramming within pancreatic islets, decreases weight gain and enhances glucose metabolism in mice fed a high-fat diet. Our study not only illustrates that intra-islet lipid signalling contributes to islet macrophage reprogramming but also provides a broadly applicable strategy for the identification of important G-protein-coupled receptor targets in pathophysiological processes, followed by the rational design of therapeutic leads for refractory diseases such as diabetes. | |||||||||
History |
|
-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
---|
-Downloads & links
-Download
PDBx/mmCIF format | 8hvi.cif.gz | 241 KB | Display | PDBx/mmCIF format |
---|---|---|---|---|
PDB format | pdb8hvi.ent.gz | 182.2 KB | Display | PDB format |
PDBx/mmJSON format | 8hvi.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8hvi_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
---|---|---|---|---|
Full document | 8hvi_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8hvi_validation.xml.gz | 39.6 KB | Display | |
Data in CIF | 8hvi_validation.cif.gz | 59.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/hv/8hvi ftp://data.pdbj.org/pub/pdb/validation_reports/hv/8hvi | HTTPS FTP |
-Related structure data
Related structure data | 35044MC 8hqeC 8hqmC 8hqnC M: map data used to model this data C: citing same article (ref.) |
---|---|
Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
|
---|---|
1 |
|
-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCD
#2: Protein | Mass: 40445.059 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P63096 |
---|---|
#3: Protein | Mass: 39489.160 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P62873 |
#4: Protein | Mass: 6375.332 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P59768 |
-Protein / Antibody / Non-polymers , 3 types, 3 molecules RH
#1: Protein | Mass: 57125.316 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human) Gene: cybC, GPR132, G2A / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P0ABE7, UniProt: Q9UNW8 |
---|---|
#5: Antibody | Mass: 26610.615 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Baculovirus expression vector pFastBac1-HM |
#6: Chemical | ChemComp-NFI / |
-Details
Has ligand of interest | Y |
---|
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
---|---|
EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: Cryo-EM structure of the apo-GPR132-Gi / Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES |
---|---|
Molecular weight | Value: 160 kDa/nm / Experimental value: YES |
Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Baculovirus expression vector pFastBac1-HM |
Buffer solution | pH: 7.5 |
Specimen | Conc.: 5 mg/ml / 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 |
---|---|
Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: SPOT SCAN |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 60 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
-Processing
Software | Name: PHENIX / Version: 1.20.1_4487: / Classification: refinement |
---|---|
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
3D reconstruction | Resolution: 3.04 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 399715 / Symmetry type: POINT |