+Open data
-Basic information
Entry | Database: PDB / ID: 8tb7 | ||||||
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Title | Cryo-EM Structure of GPR61- | ||||||
Components |
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Keywords | SIGNALING PROTEIN / GPCR / inverse agonist / membrane protein / BRIL | ||||||
Function / homology | Function and homology information ligand-independent adenylate cyclase-activating G protein-coupled receptor signaling pathway / arrestin family protein binding / G protein-coupled receptor activity / electron transport chain / periplasmic space / electron transfer activity / receptor complex / endosome membrane / endosome / iron ion binding ...ligand-independent adenylate cyclase-activating G protein-coupled receptor signaling pathway / arrestin family protein binding / G protein-coupled receptor activity / electron transport chain / periplasmic space / electron transfer activity / receptor complex / endosome membrane / endosome / iron ion binding / G protein-coupled receptor signaling pathway / heme binding / plasma membrane Similarity search - Function | ||||||
Biological species | Homo sapiens (human) Escherichia coli (E. coli) Lama glama (llama) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.94 Å | ||||||
Authors | Lees, J.A. / Dias, J.M. / Han, S. | ||||||
Funding support | 1items
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Citation | Journal: Nat Commun / Year: 2023 Title: An inverse agonist of orphan receptor GPR61 acts by a G protein-competitive allosteric mechanism. Authors: Joshua A Lees / João M Dias / Francis Rajamohan / Jean-Philippe Fortin / Rebecca O'Connor / Jimmy X Kong / Emily A G Hughes / Ethan L Fisher / Jamison B Tuttle / Gabrielle Lovett / Bethany ...Authors: Joshua A Lees / João M Dias / Francis Rajamohan / Jean-Philippe Fortin / Rebecca O'Connor / Jimmy X Kong / Emily A G Hughes / Ethan L Fisher / Jamison B Tuttle / Gabrielle Lovett / Bethany L Kormos / Rayomand J Unwalla / Lei Zhang / Anne-Marie Dechert Schmitt / Dahui Zhou / Michael Moran / Kimberly A Stevens / Kimberly F Fennell / Alison E Varghese / Andrew Maxwell / Emmaline E Cote / Yuan Zhang / Seungil Han / Abstract: GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body ...GPR61 is an orphan GPCR related to biogenic amine receptors. Its association with phenotypes relating to appetite makes it of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, the lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study GPR61 structure and function. Here, we report a structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its allosteric binding site and mode of action. These findings offer mechanistic insights into an orphan GPCR while providing both a structural framework and tool compound to support further studies of GPR61 function and modulation. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8tb7.cif.gz | 312.7 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8tb7.ent.gz | 247.8 KB | Display | PDB format |
PDBx/mmJSON format | 8tb7.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8tb7_validation.pdf.gz | 1.2 MB | Display | wwPDB validaton report |
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Full document | 8tb7_full_validation.pdf.gz | 1.2 MB | Display | |
Data in XML | 8tb7_validation.xml.gz | 38.2 KB | Display | |
Data in CIF | 8tb7_validation.cif.gz | 56.8 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/tb/8tb7 ftp://data.pdbj.org/pub/pdb/validation_reports/tb/8tb7 | HTTPS FTP |
-Related structure data
Related structure data | 41145MC 8tb0C 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
-Protein , 1 types, 1 molecules R
#1: Protein | Mass: 59991.902 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: GPR61, cybC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q9BZJ8, UniProt: P0ABE7 |
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-Antibody , 3 types, 3 molecules HNL
#2: Antibody | Mass: 52888.203 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
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#3: Antibody | Mass: 13276.541 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Lama glama (llama) / Production host: Escherichia coli (E. coli) |
#4: Antibody | Mass: 23398.066 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Production host: Homo sapiens (human) |
-Non-polymers , 2 types, 2 molecules
#5: Chemical | ChemComp-ZOB / |
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#6: Water | ChemComp-HOH / |
-Details
Has ligand of interest | Y |
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-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: GPR61-ICL3-BRIL chimera in complex with anti-BRIL Fab24 BAK5 and hinge-binding nanobody bound to inverse agonist Compound 1 Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT |
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Molecular weight | Experimental value: NO |
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: 2400 nm / Nominal defocus min: 600 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: FEI FALCON IV (4k x 4k) |
-Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
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3D reconstruction | Resolution: 2.94 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 170451 / Symmetry type: POINT | ||||||||||||||||||||||||
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