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- EMDB-23280: 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: EMDB / ID: EMD-23280 | |||||||||
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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 | |||||||||
![]() | Final masked map | |||||||||
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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 | single particle reconstruction / cryo EM / Resolution: 3.2 Å | |||||||||
![]() | Draper-Joyce CJ / Danev R / Thal DM / 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
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 6.7 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 23.2 KB 23.2 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.2 KB | Display | ![]() |
Images | ![]() | 187.9 KB | ||
Masks | ![]() | 64 MB | ![]() | |
Others | ![]() ![]() ![]() | 49.2 MB 49.6 MB 49.6 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7ld3MC ![]() 7ld4C M: atomic model generated by this map C: citing same article ( |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Final masked map | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Voxel size | X=Y=Z: 0.826 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
-Mask #1
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Density Histograms |
-Additional map: Final Refine3D map
File | emd_23280_additional_1.map | ||||||||||||
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Annotation | Final Refine3D map | ||||||||||||
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Density Histograms |
-Half map: Final Refine3D halfmap 1
File | emd_23280_half_map_1.map | ||||||||||||
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Annotation | Final Refine3D halfmap 1 | ||||||||||||
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Density Histograms |
-Half map: Final Refine3D halfmap 1
File | emd_23280_half_map_2.map | ||||||||||||
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Annotation | Final Refine3D halfmap 1 | ||||||||||||
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Density Histograms |
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Sample components
-Entire : Human adenosine A1 receptor-Gi2-protein complex bound to its endo...
Entire | Name: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine |
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Components |
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-Supramolecule #1: Human adenosine A1 receptor-Gi2-protein complex bound to its endo...
Supramolecule | Name: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 |
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Source (natural) | Organism: ![]() |
Recombinant expression | Organism: ![]() |
-Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-2
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-2 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 40.502863 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MGCTVSAEDK AAAERSKMID KNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEDG YSEEECRQYR AVVYSNTIQS IMAIVKAMG NLQIDFADPS RADDARQLFA LSCTAEEQGV LPDDLSGVIR RLWADHGVQA CFGRSREYQL NDSAAYYLND L ERIAQSDY ...String: MGCTVSAEDK AAAERSKMID KNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEDG YSEEECRQYR AVVYSNTIQS IMAIVKAMG NLQIDFADPS RADDARQLFA LSCTAEEQGV LPDDLSGVIR RLWADHGVQA CFGRSREYQL NDSAAYYLND L ERIAQSDY IPTQQDVLRT RVKTTGIVET HFTFKDLHFK MFDVGAQRSE RKKWIHCFEG VTAIIFCVAL SAYDLVLAED EE MNRMHAS MKLFDSICNN KWFTDTSIIL FLNKKDLFEE KITHSPLTIC FPEYTGANKY DEAASYIQSK FEDLNKRKDT KEI YTHFTC STDTKNVQFV FDAVTDVIIK NNLKDCGLF |
-Macromolecule #2: Chimera protein of Muscarinic acetylcholine receptor M4 and Adeno...
Macromolecule | Name: Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1 type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 43.26102 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MKTIIALSYI FCLVFADYKD DDDAMGANFT PVNGSSGNQS VRLVTSSSLE VLFQGPPPSI SAFQAAYIGI EVLIALVSVP GNVLVIWAV KVNQALRDAT FCFIVSLAVA DVAVGALVIP LAILINIGPQ TYFHTCLMVA CPVLILTQSS ILALLAIAVD R YLRVKIPL ...String: MKTIIALSYI FCLVFADYKD DDDAMGANFT PVNGSSGNQS VRLVTSSSLE VLFQGPPPSI SAFQAAYIGI EVLIALVSVP GNVLVIWAV KVNQALRDAT FCFIVSLAVA DVAVGALVIP LAILINIGPQ TYFHTCLMVA CPVLILTQSS ILALLAIAVD R YLRVKIPL RYKMVVTPRR AAVAIAGCWI LSFVVGLTPM FGWNNLSAVE RAWAANGSMG EPVIKCEFEK VISMEYMVYF NF FVWVLPP LLLMVLIYLE VFYLIRKQLN KKVSASSGDP QKYYGKELKI AKSLALILFL FALSWLPLHI LNCITLFCPS CHK PSILTY IAIFLTHGNS AMNPIVYAFR IQKFRVTFLK IWNDHFRCQP APPIDEDLPE ERPDDHHHHH H |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 38.534062 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV ...String: MHHHHHHGSS GSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKL IIWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC R FLDDNQIV TSSGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD IN AICFFPN GNAFATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAG HDNRVS CLGVTDDGMA VATGSWDSFL KIWN |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #5: ADENOSINE
Macromolecule | Name: ADENOSINE / type: ligand / ID: 5 / Number of copies: 1 / Formula: ADN |
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Molecular weight | Theoretical: 267.241 Da |
Chemical component information | ![]() ChemComp-ADN: |
-Macromolecule #6: {2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiophen-3-yl}(4-chlor...
Macromolecule | Name: {2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiophen-3-yl}(4-chlorophenyl)methanone type: ligand / ID: 6 / Number of copies: 1 / Formula: XTD |
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Molecular weight | Theoretical: 449.797 Da |
Chemical component information | ![]() ChemComp-XTD: |
-Macromolecule #7: water
Macromolecule | Name: water / type: ligand / ID: 7 / Number of copies: 1 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Buffer | pH: 7.5 |
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Vitrification | Cryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Detector mode: COUNTING / Digitization - Dimensions - Width: 3838 pixel / Digitization - Dimensions - Height: 3710 pixel / Average exposure time: 8.0 sec. / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: OTHER / Imaging mode: BRIGHT FIELD |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |