+Open data
-Basic information
Entry | Database: PDB / ID: 8x17 | ||||||
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Title | Cryo-EM structure of adenosine receptor A3AR bound to CF102 | ||||||
Components |
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Keywords | MEMBRANE PROTEIN / GPCR / adenosine A3 receptor / ligand selectivity / CF102 | ||||||
Function / homology | Function and homology information Adenylate cyclase inhibitory pathway / regulation of norepinephrine secretion / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / G protein-coupled adenosine receptor signaling pathway / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste ...Adenylate cyclase inhibitory pathway / regulation of norepinephrine secretion / Adenosine P1 receptors / G protein-coupled adenosine receptor activity / G protein-coupled adenosine receptor signaling pathway / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Ca2+ pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Glucagon-type ligand receptors / G alpha (12/13) signalling events / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / alkylglycerophosphoethanolamine phosphodiesterase activity / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thrombin signalling through proteinase activated receptors (PARs) / Ca2+ pathway / Extra-nuclear estrogen signaling / G alpha (z) signalling events / G alpha (s) signalling events / G alpha (q) signalling events / negative regulation of NF-kappaB transcription factor activity / photoreceptor outer segment membrane / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of heart contraction / activation of adenylate cyclase activity / spectrin binding / Vasopressin regulates renal water homeostasis via Aquaporins / photoreceptor outer segment / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / G protein-coupled serotonin receptor binding / cellular response to forskolin / regulation of mitotic spindle organization / cardiac muscle cell apoptotic process / presynaptic modulation of chemical synaptic transmission / photoreceptor inner segment / G-protein beta/gamma-subunit complex binding / negative regulation of cell migration / G protein-coupled receptor binding / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Schaffer collateral - CA1 synapse / response to wounding / cellular response to catecholamine stimulus / sensory perception of taste / adenylate cyclase-activating dopamine receptor signaling pathway / GDP binding / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / signaling receptor complex adaptor activity / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / GTPase binding / retina development in camera-type eye / presynaptic membrane / cell cortex / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / G alpha (i) signalling events / midbody / cell body / cell population proliferation / inflammatory response / G protein-coupled receptor signaling pathway / negative regulation of cell population proliferation / cell division / GTPase activity / centrosome / dendrite / synapse / GTP binding / protein-containing complex binding Similarity search - Function | ||||||
Biological species | Rattus norvegicus (Norway rat) Homo sapiens (human) Bos taurus (cattle) Mus musculus (house mouse) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.19 Å | ||||||
Authors | Cai, H. / Xu, Y. / Xu, H.E. | ||||||
Funding support | China, 1items
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Citation | Journal: Nat Commun / Year: 2024 Title: Cryo-EM structures of adenosine receptor AAR bound to selective agonists. Authors: Hongmin Cai / Shimeng Guo / Youwei Xu / Jun Sun / Junrui Li / Zhikan Xia / Yi Jiang / Xin Xie / H Eric Xu / Abstract: The adenosine A receptor (AAR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective AAR agonists, CF101 ...The adenosine A receptor (AAR), a key member of the G protein-coupled receptor family, is a promising therapeutic target for inflammatory and cancerous conditions. The selective AAR agonists, CF101 and CF102, are clinically significant, yet their recognition mechanisms remained elusive. Here we report the cryogenic electron microscopy structures of the full-length human AAR bound to CF101 and CF102 with heterotrimeric G protein in complex at 3.3-3.2 Å resolution. These agonists reside in the orthosteric pocket, forming conserved interactions via their adenine moieties, while their 3-iodobenzyl groups exhibit distinct orientations. Functional assays reveal the critical role of extracellular loop 3 in AAR's ligand selectivity and receptor activation. Key mutations, including His, Ser, and Ser, in a unique sub-pocket of AAR, significantly impact receptor activation. Comparative analysis with the inactive AAR structure highlights a conserved receptor activation mechanism. Our findings provide comprehensive insights into the molecular recognition and signaling of AAR, paving the way for designing subtype-selective adenosine receptor ligands. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8x17.cif.gz | 211.1 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8x17.ent.gz | 162.2 KB | Display | PDB format |
PDBx/mmJSON format | 8x17.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Summary document | 8x17_validation.pdf.gz | 1.3 MB | Display | wwPDB validaton report |
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Full document | 8x17_full_validation.pdf.gz | 1.3 MB | Display | |
Data in XML | 8x17_validation.xml.gz | 40.6 KB | Display | |
Data in CIF | 8x17_validation.cif.gz | 59.7 KB | Display | |
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/x1/8x17 ftp://data.pdbj.org/pub/pdb/validation_reports/x1/8x17 | HTTPS FTP |
-Related structure data
Related structure data | 37986MC 8x16C 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
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules BCA
#1: Protein | Mass: 37915.496 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Rattus norvegicus (Norway rat) / Gene: Gnb1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311 |
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#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Bos taurus (cattle) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63212 |
#5: Protein | Mass: 40445.059 Da / Num. of mol.: 1 / Mutation: G203A,A326S Source method: isolated from a genetically manipulated source Source: (gene. exp.) Bos taurus (cattle) / Gene: GNAI1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63097 |
-Protein / Antibody / Non-polymers , 3 types, 3 molecules RH
#2: Protein | Mass: 36214.465 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: ADORA3 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P0DMS8 |
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#4: Antibody | Mass: 26277.299 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Mus musculus (house mouse) / Production host: Trichoplusia ni (cabbage looper) |
#6: Chemical | ChemComp-XS0 / Mass: 544.731 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H18ClIN6O4 / Feature type: SUBJECT OF INVESTIGATION |
-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 |
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Molecular weight | Value: 0.16 MDa / Experimental value: NO | ||||||||||||||||||||||||||||||||||||
Source (natural) |
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Source (recombinant) | Organism: Trichoplusia ni (cabbage looper) | ||||||||||||||||||||||||||||||||||||
Buffer solution | pH: 7.5 | ||||||||||||||||||||||||||||||||||||
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES | ||||||||||||||||||||||||||||||||||||
Specimen support | Grid material: COPPER / Grid mesh size: 300 divisions/in. / Grid type: Quantifoil R1.2/1.3 | ||||||||||||||||||||||||||||||||||||
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: 5000 nm / Nominal defocus min: 1200 nm |
Image recording | Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
CTF correction | Type: NONE |
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3D reconstruction | Resolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 102581 / Symmetry type: POINT |