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- PDB-7ld3: Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein ... -
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Open data
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Basic information
Entry | Database: PDB / ID: 7ld3 | |||||||||
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Title | Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist and an allosteric ligand | |||||||||
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![]() | SIGNALING PROTEIN / membrane protein / active-state G protein-coupled receptor / adenosine A1 receptor / PAM / allosteric modulator | |||||||||
Function / homology | ![]() positive regulation of nucleoside transport / negative regulation of neurotrophin production / regulation of glomerular filtration / negative regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of peptide secretion / negative regulation of mucus secretion / purine nucleoside binding / negative regulation of glutamate secretion / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / negative regulation of long-term synaptic depression ...positive regulation of nucleoside transport / negative regulation of neurotrophin production / regulation of glomerular filtration / negative regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of peptide secretion / negative regulation of mucus secretion / purine nucleoside binding / negative regulation of glutamate secretion / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway involved in heart process / 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 / Adenosine P1 receptors / G protein-coupled acetylcholine receptor activity / heterotrimeric G-protein binding / mucus secretion / G protein-coupled adenosine receptor activity / regulation of respiratory gaseous exchange by nervous system process / negative regulation of leukocyte migration / regulation of presynaptic cytosolic calcium ion concentration / positive regulation of systemic arterial blood pressure / regulation of sensory perception of pain / G protein-coupled adenosine receptor signaling pathway / 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 / negative regulation of synaptic transmission, glutamatergic / G protein-coupled serotonin receptor activity / positive regulation of neural precursor cell proliferation / negative regulation of systemic arterial blood pressure / regulation of cardiac muscle cell contraction / gamma-aminobutyric acid signaling pathway / triglyceride homeostasis / negative regulation of synaptic transmission / protein targeting to membrane / long-term synaptic depression / regulation of locomotion / temperature homeostasis / leukocyte migration / neuronal dense core vesicle / presynaptic active zone / negative regulation of acute inflammatory response / detection of temperature stimulus involved in sensory perception of pain / regulation of calcium ion transport / calyx of Held / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / negative regulation of apoptotic signaling pathway / negative regulation of long-term synaptic potentiation / asymmetric synapse / axolemma / : / Adenylate cyclase inhibitory pathway / fatty acid homeostasis / negative regulation of lipid catabolic process / phagocytosis / lipid catabolic process / positive regulation of insulin receptor signaling pathway / : / positive regulation of vascular associated smooth muscle cell proliferation / heat shock protein binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / response to nutrient / excitatory postsynaptic potential / 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 / adenylate cyclase-activating G protein-coupled receptor signaling pathway / terminal bouton / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / 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 / cognition / 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 Similarity search - Function | |||||||||
Biological species | ![]() | |||||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
![]() | Draper-Joyce, C.J. / Danev, R. / Thal, D.M. / Christopoulos, A. / Glukhova, A. | |||||||||
Funding support | ![]()
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![]() | ![]() 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 |
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Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 169.5 KB | Display | ![]() |
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PDB format | ![]() | 134.2 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Arichive directory | ![]() ![]() | HTTPS FTP |
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-Related structure data
Related structure data | ![]() 23280MC ![]() 7ld4C M: map data used to model this data C: citing same article ( |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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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.) ![]() ![]() |
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#3: Protein | Mass: 38534.062 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
#4: Protein | Mass: 7861.143 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
-Protein , 1 types, 1 molecules R
#2: Protein | Mass: 43261.020 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() |
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-Non-polymers , 3 types, 3 molecules ![](data/chem/img/ADN.gif)
![](data/chem/img/XTD.gif)
![](data/chem/img/HOH.gif)
![](data/chem/img/XTD.gif)
![](data/chem/img/HOH.gif)
#5: Chemical | ChemComp-ADN / |
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#6: Chemical | ChemComp-XTD / { |
#7: 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 |
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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: ![]() |
Source (recombinant) | Organism: ![]() |
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 |
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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: ![]() |
Electron lens | Mode: BRIGHT FIELD |
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 K3 (6k x 4k) |
Image scans | Width: 3838 / Height: 3710 / Movie frames/image: 50 |
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Processing
CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION |
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3D reconstruction | Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 683928 / Symmetry type: POINT |