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- EMDB-33924: Cryo-EM structure of Nb29-alpha1AAR-miniGsq complex bound to oxym... -

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Basic information

Entry
Database: EMDB / ID: EMD-33924
TitleCryo-EM structure of Nb29-alpha1AAR-miniGsq complex bound to oxymetazoline
Map data
Sample
  • Complex: Nb29-alpha1AAR-miniGsq complex
    • Complex: Nb29
      • Protein or peptide: nanobody 29
    • Complex: alpha1AAR
      • Protein or peptide: alpha1A adrenergic receptor
    • Complex: miniGsq
      • Protein or peptide: miniGsq
  • Ligand: Oxymetazoline
  • Ligand: CHOLESTEROL HEMISUCCINATE
KeywordsGPCR / Nanobody / Agonist / Complex / MEMBRANE PROTEIN
Biological speciessynthetic construct (others) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.92 Å
AuthorsToyoda Y / Zhu A / Yan C / Kobilka BK / Liu X
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32122041 China
CitationJournal: Nat Commun / Year: 2023
Title: Structural basis of α-adrenergic receptor activation and recognition by an extracellular nanobody.
Authors: Yosuke Toyoda / Angqi Zhu / Fang Kong / Sisi Shan / Jiawei Zhao / Nan Wang / Xiaoou Sun / Linqi Zhang / Chuangye Yan / Brian K Kobilka / Xiangyu Liu /
Abstract: The αadrenergic receptor (αAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. αAR is involved in smooth muscle contraction and cognitive ...The αadrenergic receptor (αAR) belongs to the family of G protein-coupled receptors that respond to adrenaline and noradrenaline. αAR is involved in smooth muscle contraction and cognitive function. Here, we present three cryo-electron microscopy structures of human αAR bound to the endogenous agonist noradrenaline, its selective agonist oxymetazoline, and the antagonist tamsulosin, with resolutions range from 2.9 Å to 3.5 Å. Our active and inactive αAR structures reveal the activation mechanism and distinct ligand binding modes for noradrenaline compared with other adrenergic receptor subtypes. In addition, we identified a nanobody that preferentially binds to the extracellular vestibule of αAR when bound to the selective agonist oxymetazoline. These results should facilitate the design of more selective therapeutic drugs targeting both orthosteric and allosteric sites in this receptor family.
History
DepositionJul 27, 2022-
Header (metadata) releaseJul 5, 2023-
Map releaseJul 5, 2023-
UpdateJul 2, 2025-
Current statusJul 2, 2025Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33924.png

Downloads & links

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Map

FileDownload / File: emd_33924.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.08 Å/pix.
x 256 pix.
= 277.12 Å		1.08 Å/pix.
x 256 pix.
= 277.12 Å		1.08 Å/pix.
x 256 pix.
= 277.12 Å

Surface

Projections

Slices (1/3)

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.0825 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 1.0
Minimum - Maximum-4.906616 - 7.981617
Average (Standard dev.)0.00059857185 (±0.10858127)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 277.12 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33924_half_map_1.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33924_half_map_2.map
Projections & Slices
AxesZYX

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Histogram

Histogram (log scale)

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Sample components

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Entire : Nb29-alpha1AAR-miniGsq complex

EntireName: Nb29-alpha1AAR-miniGsq complex
Components
  • Complex: Nb29-alpha1AAR-miniGsq complex
    • Complex: Nb29
      • Protein or peptide: nanobody 29
    • Complex: alpha1AAR
      • Protein or peptide: alpha1A adrenergic receptor
    • Complex: miniGsq
      • Protein or peptide: miniGsq
  • Ligand: Oxymetazoline
  • Ligand: CHOLESTEROL HEMISUCCINATE

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Supramolecule #1: Nb29-alpha1AAR-miniGsq complex

SupramoleculeName: Nb29-alpha1AAR-miniGsq complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3

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Supramolecule #2: Nb29

SupramoleculeName: Nb29 / type: complex / ID: 2 / Parent: 1 / Macromolecule list: #3
Source (natural)Organism: synthetic construct (others)

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Supramolecule #3: alpha1AAR

SupramoleculeName: alpha1AAR / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: miniGsq

SupramoleculeName: miniGsq / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: miniGsq

MacromoleculeName: miniGsq / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.571365 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGHHHHHHHH LEVLFQGPIE KQLQKDKQVY RATHRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String:
MGHHHHHHHH LEVLFQGPIE KQLQKDKQVY RATHRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV

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Macromolecule #2: alpha1A adrenergic receptor

MacromoleculeName: alpha1A adrenergic receptor / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 53.736715 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAMVFLSG QASDSSQCTQ PPAPVQISKA ILLGVILGGL ILFGVLGNIL VILSVACHRH LHSVTHYYI VNLAVADLLL TSTVLPFSAI FEVLGYWAFG RVFCNIWAAV DVLCCTASIM GLCIISIDRY IGVSYPLRYP T IVTQRRGL ...String:
MKTIIALSYI FCLVFADYKD DDDAMVFLSG QASDSSQCTQ PPAPVQISKA ILLGVILGGL ILFGVLGNIL VILSVACHRH LHSVTHYYI VNLAVADLLL TSTVLPFSAI FEVLGYWAFG RVFCNIWAAV DVLCCTASIM GLCIISIDRY IGVSYPLRYP T IVTQRRGL MALLCVWALS LVISIGPLFG WRQPAPEDET ICQINEEPGY VLFSALGSFY LPLAIILVMY CRVYVVAKRE SR GLKSGLN IFEMLRIDEG GGSGGDEAEK LFNQDVDAAV RGILRNAKLK PVYDSLDAVR RAALINMVFQ MGETGVAGFT NSL RMLQQK RWDEAAVNLA KSRWYNQTPN RAKRVITTFR TGTWDAYLKF SREKKAAKTL GIVVGCFVLC WLPFFLVMPI GSFF PDFKP SETVFKIVFW LGYLNSCINP IIYPCSSQEF KKAFQNVLRI QCLCRKQSSK HALGYTLHPP SQAVEGQHHH HHHHH

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Macromolecule #3: nanobody 29

MacromoleculeName: nanobody 29 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 15.815713 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MKYLLPTAAA GLLLLAAQPA MAQVQLQESG GGLVQAGGSL RLSCAASGNI SAHWKMGWYR QAPGKEREFV AGIGYANTNY ADSVKGRFT ISRDNAKNTV YLQMNSLKPE DTAVYYCAAY SYYRDHSYWG QGTQVTVSSH HHHHH

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Macromolecule #4: Oxymetazoline

MacromoleculeName: Oxymetazoline / type: ligand / ID: 4 / Number of copies: 1 / Formula: J5C
Molecular weightTheoretical: 260.375 Da
Chemical component information

ChemComp-J5C:
Oxymetazoline

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Macromolecule #5: CHOLESTEROL HEMISUCCINATE

MacromoleculeName: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 5 / Number of copies: 1 / Formula: Y01
Molecular weightTheoretical: 486.726 Da
Chemical component information

ChemComp-Y01:
CHOLESTEROL HEMISUCCINATE

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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
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN 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: 1.3 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: OTHER
Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.92 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 359000
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC

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