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- EMDB-33930: Cryo-EM structure of alpha1AAR-Nb6 complex bound to tamsulosin -

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Basic information

Entry
Database: EMDB / ID: EMD-33930
TitleCryo-EM structure of alpha1AAR-Nb6 complex bound to tamsulosin
Map data
Sample
  • Complex: alpha1AAR-Nb6 complex
    • Complex: alpha1AAR
      • Protein or peptide: alpha1A-adrenergic receptor
    • Complex: Nb6
      • Protein or peptide: Nb6
  • Ligand: Tamsulosin
KeywordsGPCR / Nanobody / Antagonist / Complex / MEMBRANE PROTEIN
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.35 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_33930.png

Downloads & links

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Map

FileDownload / File: emd_33930.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 1.0
Minimum - Maximum-7.1780367 - 10.064577
Average (Standard dev.)-0.0021193782 (±0.16977732)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 220.16 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #1

Fileemd_33930_half_map_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: #2

Fileemd_33930_half_map_2.map
Projections & Slices
AxesZYX

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Slices (1/2)
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Histogram

Histogram (log scale)

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Sample components

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Entire : alpha1AAR-Nb6 complex

EntireName: alpha1AAR-Nb6 complex
Components
  • Complex: alpha1AAR-Nb6 complex
    • Complex: alpha1AAR
      • Protein or peptide: alpha1A-adrenergic receptor
    • Complex: Nb6
      • Protein or peptide: Nb6
  • Ligand: Tamsulosin

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Supramolecule #1: alpha1AAR-Nb6 complex

SupramoleculeName: alpha1AAR-Nb6 complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#2

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Supramolecule #2: alpha1AAR

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

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Supramolecule #3: Nb6

SupramoleculeName: Nb6 / type: complex / ID: 3 / Parent: 1 / Macromolecule list: #2
Source (natural)Organism: Lama glama (llama)

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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: 40.80418 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAMVFLSG QASDSSQCTQ PPAPVQISKA ILLGVILGGL ILFGVLGNIL VILSVACHRH LHSVTHYYI VNLAVADLLL TSTVLPFSAI FEVLGYWAFG RVFCNIWAAV DVLCCTARIW GLCIISIDRY IGVSYPLRYP T IVTQRRGL ...String:
MKTIIALSYI FCLVFADYKD DDDAMVFLSG QASDSSQCTQ PPAPVQISKA ILLGVILGGL ILFGVLGNIL VILSVACHRH LHSVTHYYI VNLAVADLLL TSTVLPFSAI FEVLGYWAFG RVFCNIWAAV DVLCCTARIW GLCIISIDRY IGVSYPLRYP T IVTQRRGL MALLCVWALS LVISIGPLFG WRQPAPEDET ICQINEEPGY VLFSALGSFY LPLAIILVMY TLMILRLKSV RL LSGSREK DRNLRRITRL VLIVVGCFVL CWLPFFLVMP IGSFFPDFKP SETVFKIVFW LGYLNSCINP IIYPCSSQEF KKA FQNVLR IQCLCRKQSS KHALGYTLHP PSQAVEGQHH HHHHHH

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Macromolecule #2: Nb6

MacromoleculeName: Nb6 / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 16.51559 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MKYLLPTAAA GLLLLAAQPA MAMAQVQLQE SGGGLVQAGE SLRLSCAASG TIFRLYDMGW YRRVSGNQRE LVASITSGGS TKYGDSVKG RFTISRDNAK NTVYLQMSSL KPEDTAVYYC NAEYRTGIWE ELLDGWGQGT QVTVSSHHHH HH

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Macromolecule #3: Tamsulosin

MacromoleculeName: Tamsulosin / type: ligand / ID: 3 / Number of copies: 1 / Formula: JGX
Molecular weightTheoretical: 408.512 Da
Chemical component information

ChemComp-JGX:
Tamsulosin

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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: FEI FALCON IV (4k 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: 3.35 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 285000

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