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- EMDB-33928: Cryo-EM structure of Nb29-alpha1AAR-miniGsq complex bound to nora... -

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Basic information

Entry
Database: EMDB / ID: EMD-33928
TitleCryo-EM structure of Nb29-alpha1AAR-miniGsq complex bound to noradrenaline
Map data
Sample
  • Complex: Nb29-alpha1AAR-miniGsq complex
    • Complex: Nb29
      • Protein or peptide: Nb29
    • Complex: alpha1AAR
      • Protein or peptide: alpha1A-adrenergic receptor
    • Complex: miniGsq
      • Protein or peptide: miniGsq
  • Ligand: Noradrenaline
KeywordsGPCR / Nanobody / Agonist / Complex / MEMBRANE PROTEIN
Biological speciessynthetic construct (others) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.52 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 28, 2022-
Header (metadata) releaseJul 5, 2023-
Map releaseJul 5, 2023-
UpdateJul 5, 2023-
Current statusJul 5, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_33928.png

Downloads & links

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Map

FileDownload / File: emd_33928.map.gz / Format: CCP4 / Size: 42.9 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.0979 Å
Density
Contour LevelBy AUTHOR: 0.5
Minimum - Maximum-1.9301094 - 2.7386477
Average (Standard dev.)-0.00003671337 (±0.050604325)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions224224224
Spacing224224224
CellA=B=C: 245.92961 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_33928_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #1

Fileemd_33928_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
Density Histograms

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: Nb29
    • Complex: alpha1AAR
      • Protein or peptide: alpha1A-adrenergic receptor
    • Complex: miniGsq
      • Protein or peptide: miniGsq
  • Ligand: Noradrenaline

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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: #1
Source (natural)Organism: Homo sapiens (human)

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Supramolecule #4: miniGsq

SupramoleculeName: miniGsq / type: complex / ID: 4 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: alpha1A-adrenergic receptor

MacromoleculeName: alpha1A-adrenergic receptor / type: protein_or_peptide / ID: 1 / 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 #2: miniGsq

MacromoleculeName: miniGsq / type: protein_or_peptide / ID: 2 / 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 #3: Nb29

MacromoleculeName: Nb29 / 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: Noradrenaline

MacromoleculeName: Noradrenaline / type: ligand / ID: 4 / Number of copies: 1 / Formula: E5E
Molecular weightTheoretical: 170.186 Da
Chemical component information

ChemComp-E5E:
Noradrenaline / neurotransmitter, hormone*YM / Norepinephrine

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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
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 1.8 µm / Nominal defocus min: 1.3 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: OTHER
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.52 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 393000

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