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- EMDB-7835: Cryo-EM structure of the human adenosine A1 receptor-Gi2-protein ... -

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Entry
Database: EMDB / ID: EMD-7835
TitleCryo-EM structure of the human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist
Map data
Sample
  • Complex: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-2
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1
  • Ligand: ADENOSINE
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 / G protein-coupled purinergic nucleotide receptor signaling pathway / negative regulation of mucus secretion / positive regulation of peptide secretion / negative regulation of glutamate secretion / negative regulation of synaptic transmission, GABAergic ...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 / G protein-coupled purinergic nucleotide receptor signaling pathway / negative regulation of mucus secretion / positive regulation of peptide secretion / negative regulation of glutamate secretion / negative regulation of synaptic transmission, GABAergic / negative regulation of long-term synaptic depression / positive regulation of lipid catabolic process / Muscarinic acetylcholine receptors / positive regulation of dephosphorylation / G protein-coupled acetylcholine receptor activity / negative regulation of hormone secretion / negative regulation of adenylate cyclase-activating adrenergic receptor signaling pathway / negative regulation of leukocyte migration / mucus secretion / regulation of sensory perception of pain / Adenosine P1 receptors / heterotrimeric G-protein binding / G protein-coupled adenosine receptor activity / regulation of respiratory gaseous exchange by nervous system process / response to purine-containing compound / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of calcium ion-dependent exocytosis / G protein-coupled adenosine receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled acetylcholine receptor signaling pathway / positive regulation of potassium ion transport / negative regulation of adenylate cyclase activity / positive regulation of urine volume / positive regulation of neural precursor cell proliferation / negative regulation of systemic arterial blood pressure / negative regulation of synaptic transmission / negative regulation of synaptic transmission, glutamatergic / regulation of cardiac muscle cell contraction / long-term synaptic depression / presynaptic active zone / protein targeting to membrane / triglyceride homeostasis / leukocyte migration / temperature homeostasis / regulation of locomotion / gamma-aminobutyric acid signaling pathway / detection of temperature stimulus involved in sensory perception of pain / positive regulation of systemic arterial blood pressure / negative regulation of acute inflammatory response / regulation of calcium ion transport / negative regulation of long-term synaptic potentiation / negative regulation of apoptotic signaling pathway / asymmetric synapse / axolemma / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / fatty acid homeostasis / phagocytosis / neuronal dense core vesicle / negative regulation of lipid catabolic process / lipid catabolic process / positive regulation of vascular associated smooth muscle cell proliferation / positive regulation of superoxide anion generation / Adenylate cyclase inhibitory pathway / heat shock protein binding / response to nutrient / calyx of Held / hippocampal mossy fiber to CA3 synapse / excitatory postsynaptic potential / Regulation of insulin secretion / apoptotic signaling pathway / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / vasodilation / cognition / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / terminal bouton / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1
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 / G protein beta WD-40 repeat protein / 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. / 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
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)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.6 Å
AuthorsDraper-Joyce CJ / Khoshouei M
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, 2018-
Header (metadata) releaseMay 16, 2018-
Map releaseJun 20, 2018-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: RCSB / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-6d9h
  • Surface level: 0.07
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_7835.png

Downloads & links

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Map

FileDownload / File: emd_7835.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.06 Å/pix.
x 180 pix.
= 190.8 Å		1.06 Å/pix.
x 180 pix.
= 190.8 Å		1.06 Å/pix.
x 180 pix.
= 190.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.06 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.06 / Movie #1: 0.07
Minimum - Maximum-0.3844988 - 0.5573091
Average (Standard dev.)0.0012767771 (±0.016002253)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 190.79999 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.061.061.06
M x/y/z180180180
origin x/y/z0.0000.0000.000
length x/y/z190.800190.800190.800
α/β/γ90.00090.00090.000
start NX/NY/NZ-163-114-126
NX/NY/NZ210124170
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS180180180
D min/max/mean-0.3840.5570.001

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Supplemental data

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Sample components

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Entire : Human adenosine A1 receptor-Gi2-protein complex bound to its endo...

EntireName: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine
Components
  • Complex: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-2
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1
  • Ligand: ADENOSINE

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Supramolecule #1: Human adenosine A1 receptor-Gi2-protein complex bound to its endo...

SupramoleculeName: Human adenosine A1 receptor-Gi2-protein complex bound to its endogenous agonist adenosine
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-2

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-2
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.502863 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-2

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 38.534062 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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

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Macromolecule #4: Chimera protein of Muscarinic acetylcholine receptor M4 and Adeno...

MacromoleculeName: Chimera protein of Muscarinic acetylcholine receptor M4 and Adenosine receptor A1
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 43.537309 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: 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 HHH

UniProtKB: Muscarinic acetylcholine receptor M4, Adenosine receptor A1

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Macromolecule #5: ADENOSINE

MacromoleculeName: ADENOSINE / type: ligand / ID: 5 / Number of copies: 1 / Formula: ADN
Molecular weightTheoretical: 267.241 Da
Chemical component information

ChemComp-ADN:
ADENOSINE

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.5
GridModel: Quantifoil R1.2/1.3 / Material: COPPER / Mesh: 200 / Pretreatment - Type: GLOW DISCHARGE
VitrificationCryogen name: ETHANE-PROPANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K2 SUMMIT (4k 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 beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Calibrated magnification: 47170 / Illumination mode: OTHER / Imaging mode: BRIGHT FIELD
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Final reconstructionApplied symmetry - Point group: C1 (asymmetric) / Resolution.type: BY AUTHOR / Resolution: 3.6 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 263321
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: PROJECTION MATCHING

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