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- PDB-6d9h: Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein ... -

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Basic information

Entry
Database: PDB / ID: 6d9h
TitleCryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist
Components
  • Chimera protein of Muscarinic acetylcholine receptor M4 and 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
  • Guanine nucleotide-binding protein G(i) subunit alpha-2
KeywordsSIGNALING 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 / negative regulation of circadian sleep/wake cycle, non-REM sleep / regulation of glomerular filtration / purine nucleoside binding / positive regulation of peptide secretion / negative regulation of mucus secretion / negative regulation of glutamate secretion / negative regulation of long-term synaptic depression / Muscarinic acetylcholine receptors ...positive regulation of nucleoside transport / negative regulation of neurotrophin production / negative regulation of circadian sleep/wake cycle, non-REM sleep / regulation of glomerular filtration / purine nucleoside binding / positive regulation of peptide secretion / negative regulation of mucus secretion / negative regulation of glutamate secretion / negative regulation of long-term synaptic depression / Muscarinic acetylcholine receptors / G protein-coupled acetylcholine receptor activity / positive regulation of lipid catabolic process / negative regulation of synaptic transmission, GABAergic / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of hormone secretion / negative regulation of leukocyte migration / mucus secretion / heterotrimeric G-protein binding / positive regulation of dephosphorylation / Adenosine P1 receptors / regulation of respiratory gaseous exchange by nervous system process / G protein-coupled adenosine receptor activity / regulation of sensory perception of pain / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of calcium ion-dependent exocytosis / response to purine-containing compound / G protein-coupled adenosine receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / positive regulation of potassium ion transport / positive regulation of urine volume / negative regulation of adenylate cyclase activity / positive regulation of neural precursor cell proliferation / negative regulation of synaptic transmission / negative regulation of synaptic transmission, glutamatergic / negative regulation of systemic arterial blood pressure / regulation of cardiac muscle cell contraction / triglyceride homeostasis / protein targeting to membrane / long-term synaptic depression / gamma-aminobutyric acid signaling pathway / regulation of locomotion / leukocyte migration / temperature homeostasis / neuronal dense core vesicle / positive regulation of systemic arterial blood pressure / negative regulation of acute inflammatory response / detection of temperature stimulus involved in sensory perception of pain / presynaptic active zone / negative regulation of apoptotic signaling pathway / regulation of calcium ion transport / negative regulation of long-term synaptic potentiation / asymmetric synapse / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / axolemma / phagocytosis / fatty acid homeostasis / negative regulation of lipid catabolic process / Adenylate cyclase inhibitory pathway / lipid catabolic process / positive regulation of vascular associated smooth muscle cell proliferation / heat shock protein binding / response to nutrient / calyx of Held / hippocampal mossy fiber to CA3 synapse / positive regulation of superoxide anion generation / excitatory postsynaptic potential / Regulation of insulin secretion / apoptotic signaling pathway / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / terminal bouton / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / cognition / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled 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 / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / 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 / cellular response to catecholamine stimulus / vasodilation / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1
Similarity search - Function
Adenosine A1 receptor / Muscarinic acetylcholine receptor M4 / Muscarinic acetylcholine receptor family / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Adenosine receptor / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase ...Adenosine A1 receptor / Muscarinic acetylcholine receptor M4 / Muscarinic acetylcholine receptor family / Transducin (heterotrimeric G protein), gamma chain / G Protein Gi Gamma 2 / Adenosine receptor / Rhopdopsin 7-helix transmembrane proteins / Rhodopsin 7-helix transmembrane proteins / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / Few Secondary Structures / Irregular / 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. / P-loop containing nucleotide triphosphate hydrolases / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / Up-down Bundle / Rossmann fold / P-loop containing nucleoside triphosphate hydrolase / 3-Layer(aba) Sandwich / Mainly Beta / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
ADENOSINE / 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: 3.6 Å
AuthorsDraper-Joyce, C.J. / Khoshouei, M. / Thal, D.M. / Liang, Y.-L. / Nguyen, A.T.N. / Furness, S.G.B. / Venugopal, H. / Baltos, J. / Plitzko, J.M. / Danev, R. ...Draper-Joyce, C.J. / Khoshouei, M. / Thal, D.M. / Liang, Y.-L. / Nguyen, A.T.N. / Furness, S.G.B. / Venugopal, H. / Baltos, J. / Plitzko, J.M. / Danev, R. / Baumeister, W. / May, L.T. / Wootten, D. / Sexton, P. / Glukhova, A. / Christopoulos, A.
CitationJournal: Nature / Year: 2018
Title: Structure of the adenosine-bound human adenosine A receptor-G complex.
Authors: Christopher J Draper-Joyce / Maryam Khoshouei / David M Thal / Yi-Lynn Liang / Anh T N Nguyen / Sebastian G B Furness / Hariprasad Venugopal / Jo-Anne Baltos / Jürgen M Plitzko / Radostin ...Authors: Christopher J Draper-Joyce / Maryam Khoshouei / David M Thal / Yi-Lynn Liang / Anh T N Nguyen / Sebastian G B Furness / Hariprasad Venugopal / Jo-Anne Baltos / Jürgen M Plitzko / Radostin Danev / Wolfgang Baumeister / Lauren T May / Denise Wootten / Patrick M Sexton / Alisa Glukhova / Arthur Christopoulos /
Abstract: The class A adenosine A receptor (AR) is a G-protein-coupled receptor that preferentially couples to inhibitory G heterotrimeric G proteins, has been implicated in numerous diseases, yet remains ...The class A adenosine A receptor (AR) is a G-protein-coupled receptor that preferentially couples to inhibitory G heterotrimeric G proteins, has been implicated in numerous diseases, yet remains poorly targeted. Here we report the 3.6 Å structure of the human AR in complex with adenosine and heterotrimeric G protein determined by Volta phase plate cryo-electron microscopy. Compared to inactive AR, there is contraction at the extracellular surface in the orthosteric binding site mediated via movement of transmembrane domains 1 and 2. At the intracellular surface, the G protein engages the AR primarily via amino acids in the C terminus of the Gα α5-helix, concomitant with a 10.5 Å outward movement of the AR transmembrane domain 6. Comparison with the agonist-bound β adrenergic receptor-G-protein complex reveals distinct orientations for each G-protein subtype upon engagement with its receptor. This active AR structure provides molecular insights into receptor and G-protein selectivity.
History
DepositionApr 29, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 20, 2018Provider: repository / Type: Initial release
Revision 1.1Jul 4, 2018Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.pdbx_database_id_PubMed / _citation.title / _citation_author.name
Revision 1.2Jul 11, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Oct 30, 2024Group: Data collection / Database references / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _em_admin.last_update

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-2
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
R: Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)130,7035
Polymers130,4354
Non-polymers2671
Water00
1


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

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Components

#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
#2: 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
#3: 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
#4: Protein Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1


Mass: 43537.309 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
#5: Chemical ChemComp-ADN / ADENOSINE


Mass: 267.241 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H13N5O4 / Feature type: SUBJECT OF INVESTIGATION
Has protein modificationY

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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
Specimen supportGrid material: COPPER / Grid mesh size: 200 divisions/in. / Grid type: Quantifoil R1.2/1.3
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 / Calibrated magnification: 47170 X / C2 aperture diameter: 50 µm
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 K2 SUMMIT (4k x 4k)
Image scansWidth: 3838 / Height: 3710 / Movie frames/image: 50

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Processing

SoftwareName: PHENIX / Version: 1.12_2829: / Classification: refinement
CTF correctionDetails: Phase plate CTF correction / Type: NONE
SymmetryPoint symmetry: C1 (asymmetric)
3D reconstructionResolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 263321 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0067167
ELECTRON MICROSCOPYf_angle_d0.9189710
ELECTRON MICROSCOPYf_dihedral_angle_d4.1254282
ELECTRON MICROSCOPYf_chiral_restr0.0561125
ELECTRON MICROSCOPYf_plane_restr0.0071227

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