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Yorodumi- PDB-7ld4: Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein ... -
+Open data
-Basic information
Entry | Database: PDB / ID: 7ld4 | |||||||||
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Title | Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist | |||||||||
Components |
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Keywords | SIGNALING PROTEIN / membrane protein / active-state G protein-coupled receptor / adenosine A1 receptor | |||||||||
Function / homology | Function and homology information positive regulation of nucleoside transport / negative regulation of neurotrophin production / regulation of glomerular filtration / positive regulation of peptide secretion / negative regulation of circadian sleep/wake cycle, non-REM sleep / negative regulation of mucus secretion / purine nucleoside binding / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / negative regulation of glutamate secretion / negative regulation of long-term synaptic depression ...positive regulation of nucleoside transport / negative regulation of neurotrophin production / regulation of glomerular filtration / positive regulation of peptide secretion / negative regulation of circadian sleep/wake cycle, non-REM sleep / negative regulation of mucus secretion / purine nucleoside binding / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / negative regulation of glutamate secretion / negative regulation of long-term synaptic depression / negative regulation of hormone secretion / Muscarinic acetylcholine receptors / positive regulation of lipid catabolic process / negative regulation of synaptic transmission, GABAergic / regulation of presynaptic cytosolic calcium ion concentration / Adenosine P1 receptors / G protein-coupled acetylcholine receptor activity / heterotrimeric G-protein binding / G protein-coupled adenosine receptor activity / negative regulation of leukocyte migration / mucus secretion / regulation of respiratory gaseous exchange by nervous system process / G protein-coupled adenosine receptor signaling pathway / regulation of sensory perception of pain / positive regulation of systemic arterial blood pressure / negative regulation of calcium ion-dependent exocytosis / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / response to purine-containing compound / positive regulation of urine volume / positive regulation of potassium ion transport / negative regulation of adenylate cyclase activity / triglyceride homeostasis / positive regulation of neural precursor cell proliferation / negative regulation of synaptic transmission, glutamatergic / G protein-coupled serotonin receptor activity / regulation of cardiac muscle cell contraction / negative regulation of systemic arterial blood pressure / gamma-aminobutyric acid signaling pathway / negative regulation of synaptic transmission / protein targeting to membrane / long-term synaptic depression / regulation of locomotion / temperature homeostasis / presynaptic active zone / leukocyte migration / neuronal dense core vesicle / detection of temperature stimulus involved in sensory perception of pain / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / negative regulation of long-term synaptic potentiation / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / calyx of Held / negative regulation of acute inflammatory response / asymmetric synapse / Adenylate cyclase inhibitory pathway / axolemma / response to inorganic substance / fatty acid homeostasis / lipid catabolic process / negative regulation of lipid catabolic process / phagocytosis / positive regulation of insulin receptor signaling pathway / positive regulation of protein dephosphorylation / positive regulation of vascular associated smooth muscle cell proliferation / heat shock protein binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / excitatory postsynaptic potential / response to nutrient / positive regulation of superoxide anion generation / Regulation of insulin secretion / G protein-coupled receptor binding / apoptotic signaling pathway / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / terminal bouton / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / cognition / 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 Similarity search - Function | |||||||||
Biological species | Homo sapiens (human) | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å | |||||||||
Authors | Draper-Joyce, C.J. / Danev, R. / Thal, D.M. / Christopoulos, A. / Glukhova, A. | |||||||||
Funding support | Australia, 2items
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Citation | Journal: Nature / Year: 2021 Title: Positive allosteric mechanisms of adenosine A receptor-mediated analgesia. Authors: Christopher J Draper-Joyce / Rebecca Bhola / Jinan Wang / Apurba Bhattarai / Anh T N Nguyen / India Cowie-Kent / Kelly O'Sullivan / Ling Yeong Chia / Hariprasad Venugopal / Celine Valant / ...Authors: Christopher J Draper-Joyce / Rebecca Bhola / Jinan Wang / Apurba Bhattarai / Anh T N Nguyen / India Cowie-Kent / Kelly O'Sullivan / Ling Yeong Chia / Hariprasad Venugopal / Celine Valant / David M Thal / Denise Wootten / Nicolas Panel / Jens Carlsson / Macdonald J Christie / Paul J White / Peter Scammells / Lauren T May / Patrick M Sexton / Radostin Danev / Yinglong Miao / Alisa Glukhova / Wendy L Imlach / Arthur Christopoulos / Abstract: The adenosine A receptor (AR) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain. However, development of analgesic orthosteric AR agonists has failed because ...The adenosine A receptor (AR) is a promising therapeutic target for non-opioid analgesic agents to treat neuropathic pain. However, development of analgesic orthosteric AR agonists has failed because of a lack of sufficient on-target selectivity as well as off-tissue adverse effects. Here we show that [2-amino-4-(3,5-bis(trifluoromethyl)phenyl)thiophen-3-yl)(4-chlorophenyl)methanone] (MIPS521), a positive allosteric modulator of the AR, exhibits analgesic efficacy in rats in vivo through modulation of the increased levels of endogenous adenosine that occur in the spinal cord of rats with neuropathic pain. We also report the structure of the AR co-bound to adenosine, MIPS521 and a G heterotrimer, revealing an extrahelical lipid-detergent-facing allosteric binding pocket that involves transmembrane helixes 1, 6 and 7. Molecular dynamics simulations and ligand kinetic binding experiments support a mechanism whereby MIPS521 stabilizes the adenosine-receptor-G protein complex. This study provides proof of concept for structure-based allosteric drug design of non-opioid analgesic agents that are specific to disease contexts. | |||||||||
History |
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-Structure visualization
Movie |
Movie viewer |
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Structure viewer | Molecule: MolmilJmol/JSmol |
-Downloads & links
-Download
PDBx/mmCIF format | 7ld4.cif.gz | 167.9 KB | Display | PDBx/mmCIF format |
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PDB format | pdb7ld4.ent.gz | 132.3 KB | Display | PDB format |
PDBx/mmJSON format | 7ld4.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/ld/7ld4 ftp://data.pdbj.org/pub/pdb/validation_reports/ld/7ld4 | HTTPS FTP |
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-Related structure data
Related structure data | 23281MC 7ld3C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
-Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG
#1: Protein | Mass: 40502.863 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI2, GNAI2B / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P04899 |
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#2: Protein | Mass: 38534.062 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNB1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P62873 |
#3: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768 |
-Protein , 1 types, 1 molecules R
#4: Protein | Mass: 43261.020 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: CHRM4, ADORA1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P08173, UniProt: P30542 |
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-Non-polymers , 2 types, 2 molecules
#5: Chemical | ChemComp-ADN / |
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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: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
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 |
Vitrification | Instrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE-PROPANE / Humidity: 100 % / Chamber temperature: 277 K |
-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: OTHER |
Electron lens | Mode: BRIGHT FIELDBright-field microscopy / Calibrated magnification: 47170 X / C2 aperture diameter: 50 µm |
Specimen holder | Cryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER |
Image recording | Average exposure time: 8 sec. / Electron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k) |
EM imaging optics | Phase plate: VOLTA PHASE PLATE |
Image scans | Width: 3838 / Height: 3710 / Movie frames/image: 50 |
-Processing
CTF correction | Details: Phase plate CTF correction / Type: NONE |
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3D reconstruction | Resolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 716000 / Symmetry type: POINT |