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- EMDB-45425: Cryo-EM structure of epinephrine-bound alpha-2A-adrenergic recept... -

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Entry
Database: EMDB / ID: EMD-45425
TitleCryo-EM structure of epinephrine-bound alpha-2A-adrenergic receptor in complex with heterotrimeric Gi-protein
Map data
Sample
  • Complex: Epinephrine-bound alpha-2A-adrenergic receptor in complex with heterotrimeric Gi-protein
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • 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: Endolysin,Alpha-2A adrenergic receptor
  • Ligand: L-EPINEPHRINE
KeywordsGPCR / Adrenergic Receptor / SIGNALING PROTEIN
Function / homology
Function and homology information


negative regulation of uterine smooth muscle contraction / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / alpha-2C adrenergic receptor binding / negative regulation of epinephrine secretion / epinephrine binding / phospholipase C-activating adrenergic receptor signaling pathway / negative regulation of norepinephrine secretion / alpha-1B adrenergic receptor binding ...negative regulation of uterine smooth muscle contraction / adenylate cyclase-inhibiting adrenergic receptor signaling pathway / alpha2-adrenergic receptor activity / Adrenaline signalling through Alpha-2 adrenergic receptor / alpha-2C adrenergic receptor binding / negative regulation of epinephrine secretion / epinephrine binding / phospholipase C-activating adrenergic receptor signaling pathway / negative regulation of norepinephrine secretion / alpha-1B adrenergic receptor binding / Extra-nuclear estrogen signaling / Adenylate cyclase inhibitory pathway / Olfactory Signaling Pathway / Sensory perception of sweet, bitter, and umami (glutamate) taste / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / heterotrimeric G-protein binding / negative regulation of calcium ion-dependent exocytosis / Activation of the phototransduction cascade / Surfactant metabolism / dopaminergic synapse / positive regulation of potassium ion transport / thermoception / fear response / thioesterase binding / negative regulation of synaptic transmission / negative regulation of insulin secretion involved in cellular response to glucose stimulus / GTPase activating protein binding / intestinal absorption / response to alcohol / positive regulation of membrane protein ectodomain proteolysis / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / norepinephrine binding / Adrenoceptors / G alpha (i) signalling events / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of epidermal growth factor receptor signaling pathway / response to morphine / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / neurotransmitter receptor localization to postsynaptic specialization membrane / positive regulation of wound healing / adrenergic receptor signaling pathway / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / negative regulation of calcium ion transport / Rho protein signal transduction / regulation of vasoconstriction / negative regulation of lipid catabolic process / viral release from host cell by cytolysis / cellular response to hormone stimulus / positive regulation of protein localization to cell cortex / T cell migration / D2 dopamine receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / axon terminus / presynaptic active zone membrane / peptidoglycan catabolic process / presynaptic modulation of chemical synaptic transmission / cellular response to forskolin / regulation of mitotic spindle organization / guanyl-nucleotide exchange factor activity / positive regulation of cytokine production / female pregnancy / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / negative regulation of insulin secretion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / postsynaptic density membrane / GABA-ergic synapse / platelet activation / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / photoreceptor disc membrane
Similarity search - Function
Alpha 2A adrenoceptor / Adrenoceptor family / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx ...Alpha 2A adrenoceptor / Adrenoceptor family / Endolysin T4 type / T4-type lysozyme / : / Glycoside hydrolase, family 24 / Phage lysozyme / Lysozyme domain superfamily / 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. / Lysozyme-like domain superfamily / 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
Endolysin / Alpha-2A adrenergic receptor / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human) / Rattus norvegicus (Norway rat) / Bos taurus (domestic cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.8 Å
AuthorsLou JS / Su M / Wang J / Do HN / Miao Y / Huang XY
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM138676 United States
CitationJournal: Exp Mol Med / Year: 2024
Title: Distinct binding conformations of epinephrine with α- and β-adrenergic receptors.
Authors: Jian-Shu Lou / Minfei Su / Jinan Wang / Hung Nguyen Do / Yinglong Miao / Xin-Yun Huang /
Abstract: Agonists targeting α-adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, attention-deficit/hyperactivity disorder, pain, panic disorders, opioid and alcohol ...Agonists targeting α-adrenergic receptors (ARs) are used to treat diverse conditions, including hypertension, attention-deficit/hyperactivity disorder, pain, panic disorders, opioid and alcohol withdrawal symptoms, and cigarette cravings. These receptors transduce signals through heterotrimeric Gi proteins. Here, we elucidated cryo-EM structures that depict α-AR in complex with Gi proteins, along with the endogenous agonist epinephrine or the synthetic agonist dexmedetomidine. Molecular dynamics simulations and functional studies reinforce the results of the structural revelations. Our investigation revealed that epinephrine exhibits different conformations when engaging with α-ARs and β-ARs. Furthermore, α-AR and β-AR (primarily coupled to Gs, with secondary associations to Gi) were compared and found to exhibit different interactions with Gi proteins. Notably, the stability of the epinephrine-α-AR-Gi complex is greater than that of the dexmedetomidine-α-AR-Gi complex. These findings substantiate and improve our knowledge on the intricate signaling mechanisms orchestrated by ARs and concurrently shed light on the regulation of α-ARs and β-ARs by epinephrine.
History
DepositionJun 19, 2024-
Header (metadata) releaseSep 11, 2024-
Map releaseSep 11, 2024-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_45425.png

Downloads & links

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Map

FileDownload / File: emd_45425.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)X (Row.)Y (Col.)
0.86 Å/pix.
x 320 pix.
= 273.92 Å		0.86 Å/pix.
x 320 pix.
= 273.92 Å		0.86 Å/pix.
x 320 pix.
= 273.92 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.856 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.6
Minimum - Maximum-7.535771 - 10.261136
Average (Standard dev.)0.00032239745 (±0.14162803)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderYXZ
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 273.92 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Epinephrine-bound alpha-2A-adrenergic receptor in complex with he...

EntireName: Epinephrine-bound alpha-2A-adrenergic receptor in complex with heterotrimeric Gi-protein
Components
  • Complex: Epinephrine-bound alpha-2A-adrenergic receptor in complex with heterotrimeric Gi-protein
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • 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: Endolysin,Alpha-2A adrenergic receptor
  • Ligand: L-EPINEPHRINE

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Supramolecule #1: Epinephrine-bound alpha-2A-adrenergic receptor in complex with he...

SupramoleculeName: Epinephrine-bound alpha-2A-adrenergic receptor in complex with heterotrimeric Gi-protein
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-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 43.14707 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGSSHHHHHH SSGLEVLFQG PHMASMGCTL SAEDKAAVER SKMIDRNLRE DGEKAAREVK LLLLGAGESG KSTIVKQMKI IHEAGYSEE ECKQYKAVVY SNTIQSIIAI IRAMGRLKID FGDAARADDA RQLFVLAGAA EEGFMTAELA GVIKRLWKDS G VQACFNRS ...String:
MGSSHHHHHH SSGLEVLFQG PHMASMGCTL SAEDKAAVER SKMIDRNLRE DGEKAAREVK LLLLGAGESG KSTIVKQMKI IHEAGYSEE ECKQYKAVVY SNTIQSIIAI IRAMGRLKID FGDAARADDA RQLFVLAGAA EEGFMTAELA GVIKRLWKDS G VQACFNRS REYQLNDSAA YYLNDLDRIA QPNYIPTQQD VLRTRVKTTG IVETHFTFKD LHFKMFDVGA QRSERKKWIH CF EGVTAII FCVALSDYDL VLAEDEEMNR MHESMKLFDS ICNNKWFTDT SIILFLNKKD LFEEKIKKSP LTICYPEYAG SNT YEEAAA YIQCQFEDLN KRKDTKEIYT HFTCATDTKN VQFVFDAVTD VIIKNNLKDC GLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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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: Bos taurus (domestic cattle)
Molecular weightTheoretical: 37.285734 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW ...String:
SELDQLRQEA EQLKNQIRDA RKACADATLS QITNNIDPVG RIQMRTRRTL RGHLAKIYAM HWGTDSRLLV SASQDGKLII WDSYTTNKV HAIPLRSSWV MTCAYAPSGN YVACGGLDNI CSIYNLKTRE GNVRVSRELA GHTGYLSCCR FLDDNQIVTS S GDTTCALW DIETGQQTTT FTGHTGDVMS LSLAPDTRLF VSGACDASAK LWDVREGMCR QTFTGHESDI NAICFFPNGN AF ATGSDDA TCRLFDLRAD QELMTYSHDN IICGITSVSF SKSGRLLLAG YDDFNCNVWD ALKADRAGVL AGHDNRVSCL GVT DDGMAV ATGSWDSFLK IWN

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: Bos taurus (domestic cattle)
Molecular weightTheoretical: 7.845078 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFSAI L

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

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Macromolecule #4: Endolysin,Alpha-2A adrenergic receptor

MacromoleculeName: Endolysin,Alpha-2A adrenergic receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO / EC number: lysozyme
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 54.715871 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKNIFEML RIDEGLRLKI YKDTEGYYTI GIGHLLTKSP SLNAAKSELD KAIGRNTNGV ITKDEAEKL FNQDVDAAVR GILRNAKLKP VYDSLDAVRR AALINMVFQM GETGVAGFTN SLRMLQQKRW DEAAVNLAKS R WYNQTPNR ...String:
MKTIIALSYI FCLVFADYKD DDDKNIFEML RIDEGLRLKI YKDTEGYYTI GIGHLLTKSP SLNAAKSELD KAIGRNTNGV ITKDEAEKL FNQDVDAAVR GILRNAKLKP VYDSLDAVRR AALINMVFQM GETGVAGFTN SLRMLQQKRW DEAAVNLAKS R WYNQTPNR AKRVITTFRT GTWDAYAAAG GGARATPYSL QVTLTLVCLA GLLMLLTVFG NVLVIIAVFT SRALKAPQNL FL VSLASAD ILVATLVIPF SLANEVMGYW YFGKAWCEIY LALDVLFCTS SIVHLCAISL DRYWSITQAI EYNLKRTPRR IKA IIITVW VISAVISFPP LISIEKKGGG GGPQPAEPRC EINDQKWYVI SSCIGSFFAP CLIMILVYVR IYQIAKRRTR QNRE KRFTF VLAVVIGVFV VCWFPFFFTY TLTAVGCSVP RTLFKFFFWF GYCNSSLNPV IYTIFNHDFR RAFKKILCRG DASLE VLFQ

UniProtKB: Endolysin, Alpha-2A adrenergic receptor, Alpha-2A adrenergic receptor

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Macromolecule #5: L-EPINEPHRINE

MacromoleculeName: L-EPINEPHRINE / type: ligand / ID: 5 / Number of copies: 1 / Formula: ALE
Molecular weightTheoretical: 183.204 Da
Chemical component information

ChemComp-ALE:
L-EPINEPHRINE / medication, hormone*YM

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.8 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6kux

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.8 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 713558
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD

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