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- PDB-7ld3: Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein ... -

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Basic information

Entry
Database: PDB / ID: 7ld3
TitleCryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist and an allosteric ligand
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1
KeywordsSIGNALING PROTEIN / membrane protein / active-state G protein-coupled receptor / adenosine A1 receptor / PAM / allosteric modulator
Function / homology
Function and homology information


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 / Muscarinic acetylcholine receptors / positive regulation of lipid catabolic process / negative regulation of synaptic transmission, GABAergic / negative regulation of hormone secretion / Adenosine P1 receptors / mucus secretion / G protein-coupled adenosine receptor activity / regulation of respiratory gaseous exchange by nervous system process / negative regulation of leukocyte migration / heterotrimeric G-protein binding / G protein-coupled acetylcholine receptor activity / regulation of sensory perception of pain / regulation of presynaptic cytosolic calcium ion concentration / positive regulation of systemic arterial blood pressure / G protein-coupled adenosine receptor signaling pathway / response to purine-containing compound / negative regulation of calcium ion-dependent exocytosis / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / positive regulation of urine volume / positive regulation of potassium ion transport / negative regulation of adenylate cyclase activity / negative regulation of synaptic transmission, glutamatergic / positive regulation of neural precursor cell proliferation / G protein-coupled serotonin receptor activity / 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 / leukocyte migration / temperature homeostasis / neuronal dense core vesicle / negative regulation of acute inflammatory response / presynaptic active zone / detection of temperature stimulus involved in sensory perception of pain / regulation of calcium ion transport / negative regulation of apoptotic signaling pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / calyx of Held / negative regulation of long-term synaptic potentiation / asymmetric synapse / axolemma / fatty acid homeostasis / Adenylate cyclase inhibitory pathway / 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 / apoptotic signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / terminal bouton / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / 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 / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / vasodilation / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus
Similarity search - Function
Adenosine A1 receptor / Muscarinic acetylcholine receptor M4 / Muscarinic acetylcholine receptor family / Adenosine receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. ...Adenosine A1 receptor / Muscarinic acetylcholine receptor M4 / Muscarinic acetylcholine receptor family / Adenosine receptor / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 7 transmembrane receptor (rhodopsin family) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
ADENOSINE / Chem-XTD / Guanine nucleotide-binding protein G(i) subunit alpha-2 / Muscarinic acetylcholine receptor M4 / Adenosine receptor A1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsDraper-Joyce, C.J. / Danev, R. / Thal, D.M. / Christopoulos, A. / Glukhova, A.
Funding support Australia, 2items
OrganizationGrant numberCountry
National Health and Medical Research Council (NHMRC, Australia) Australia
Australian Research Council (ARC) Australia
CitationJournal: 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
DepositionJan 12, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 8, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 13, 2021Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year

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Structure visualization

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  • Deposited structure unit
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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-2
R: Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,8766
Polymers130,1594
Non-polymers7172
Water181
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-2 / Adenylate cyclase-inhibiting G alpha 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
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


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
#4: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


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

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Protein , 1 types, 1 molecules R

#2: Protein Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1


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 , 3 types, 3 molecules

#5: Chemical ChemComp-ADN / ADENOSINE


Mass: 267.241 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H13N5O4
#6: Chemical ChemComp-XTD / {2-amino-4-[3,5-bis(trifluoromethyl)phenyl]thiophen-3-yl}(4-chlorophenyl)methanone


Mass: 449.797 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H10ClF6NOS / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.5
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: 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
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: OTHER
Electron lensMode: BRIGHT FIELD
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingAverage exposure time: 8 sec. / Electron dose: 50 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K3 (6k x 4k)
Image scansWidth: 3838 / Height: 3710 / Movie frames/image: 50

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 683928 / Symmetry type: POINT

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