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- EMDB-36342: Cryo-EM structure of the beta2AR-mBRIL/1b3 Fab/Glue complex with ... -

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Basic information

Entry
Database: EMDB / ID: EMD-36342
TitleCryo-EM structure of the beta2AR-mBRIL/1b3 Fab/Glue complex with a partial agonist
Map data
Sample
  • Complex: Cryo-EM structure of the beta2AR-mBRIL/1b3 Fab/Glue complex with a partial agonist
    • Protein or peptide: Beta-2 adrenergic receptor,Soluble cytochrome b562
  • Ligand: ~{N}-[5-[(1~{R})-2-[[(2~{R})-1-(4-methoxyphenyl)propan-2-yl]amino]-1-oxidanyl-ethyl]-2-oxidanyl-phenyl]methanamide
Keywordscomplex / chimera / GPCR / membrane protein
Function / homology
Function and homology information


desensitization of G protein-coupled receptor signaling pathway by arrestin / beta2-adrenergic receptor activity / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / positive regulation of mini excitatory postsynaptic potential / positive regulation of cAMP-dependent protein kinase activity / norepinephrine binding / Adrenoceptors / heat generation / positive regulation of autophagosome maturation / positive regulation of AMPA receptor activity ...desensitization of G protein-coupled receptor signaling pathway by arrestin / beta2-adrenergic receptor activity / norepinephrine-epinephrine-mediated vasodilation involved in regulation of systemic arterial blood pressure / positive regulation of mini excitatory postsynaptic potential / positive regulation of cAMP-dependent protein kinase activity / norepinephrine binding / Adrenoceptors / heat generation / positive regulation of autophagosome maturation / positive regulation of AMPA receptor activity / activation of transmembrane receptor protein tyrosine kinase activity / negative regulation of smooth muscle contraction / positive regulation of lipophagy / response to psychosocial stress / negative regulation of multicellular organism growth / endosome to lysosome transport / adrenergic receptor signaling pathway / diet induced thermogenesis / neuronal dense core vesicle / positive regulation of protein kinase A signaling / adenylate cyclase binding / smooth muscle contraction / potassium channel regulator activity / positive regulation of bone mineralization / adenylate cyclase-activating adrenergic receptor signaling pathway / brown fat cell differentiation / regulation of sodium ion transport / bone resorption / activation of adenylate cyclase activity / response to cold / receptor-mediated endocytosis / clathrin-coated endocytic vesicle membrane / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / positive regulation of protein serine/threonine kinase activity / cellular response to amyloid-beta / Cargo recognition for clathrin-mediated endocytosis / Clathrin-mediated endocytosis / positive regulation of cold-induced thermogenesis / amyloid-beta binding / G alpha (s) signalling events / positive regulation of MAPK cascade / transcription by RNA polymerase II / electron transfer activity / lysosome / periplasmic space / cell surface receptor signaling pathway / receptor complex / early endosome / endosome membrane / Ub-specific processing proteases / endosome / iron ion binding / apical plasma membrane / heme binding / protein-containing complex binding / Golgi apparatus / protein homodimerization activity / positive regulation of transcription by RNA polymerase II / membrane / identical protein binding / nucleus / plasma membrane
Similarity search - Function
Beta 2 adrenoceptor / Adrenoceptor family / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / 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)
Similarity search - Domain/homology
Beta-2 adrenergic receptor / Soluble cytochrome b562
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsHe BB / Zhong YX / Guo Q / Tao YY
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Chem Biol / Year: 2024
Title: A method for structure determination of GPCRs in various states.
Authors: Qiong Guo / Binbin He / Yixuan Zhong / Haizhan Jiao / Yinhang Ren / Qinggong Wang / Qiangqiang Ge / Yongxiang Gao / Xiangyu Liu / Yang Du / Hongli Hu / Yuyong Tao /
Abstract: G-protein-coupled receptors (GPCRs) are a class of integral membrane proteins that detect environmental cues and trigger cellular responses. Deciphering the functional states of GPCRs induced by ...G-protein-coupled receptors (GPCRs) are a class of integral membrane proteins that detect environmental cues and trigger cellular responses. Deciphering the functional states of GPCRs induced by various ligands has been one of the primary goals in the field. Here we developed an effective universal method for GPCR cryo-electron microscopy structure determination without the need to prepare GPCR-signaling protein complexes. Using this method, we successfully solved the structures of the β-adrenergic receptor (βAR) bound to antagonistic and agonistic ligands and the adhesion GPCR ADGRL3 in the apo state. For βAR, an intermediate state stabilized by the partial agonist was captured. For ADGRL3, the structure revealed that inactive ADGRL3 adopts a compact fold and that large unusual conformational changes on both the extracellular and intracellular sides are required for activation of adhesion GPCRs. We anticipate that this method will open a new avenue for understanding GPCR structure‒function relationships and drug development.
History
DepositionMay 29, 2023-
Header (metadata) releaseSep 6, 2023-
Map releaseSep 6, 2023-
UpdateJan 3, 2024-
Current statusJan 3, 2024Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36342.png

Downloads & links

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Map

FileDownload / File: emd_36342.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Voxel sizeX=Y=Z: 1.07 Å
Density
Contour LevelBy AUTHOR: 0.522
Minimum - Maximum-4.8154283 - 6.930166
Average (Standard dev.)0.00004163945 (±0.11308034)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 299.6 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_36342_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_36342_half_map_2.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : Cryo-EM structure of the beta2AR-mBRIL/1b3 Fab/Glue complex with ...

EntireName: Cryo-EM structure of the beta2AR-mBRIL/1b3 Fab/Glue complex with a partial agonist
Components
  • Complex: Cryo-EM structure of the beta2AR-mBRIL/1b3 Fab/Glue complex with a partial agonist
    • Protein or peptide: Beta-2 adrenergic receptor,Soluble cytochrome b562
  • Ligand: ~{N}-[5-[(1~{R})-2-[[(2~{R})-1-(4-methoxyphenyl)propan-2-yl]amino]-1-oxidanyl-ethyl]-2-oxidanyl-phenyl]methanamide

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Supramolecule #1: Cryo-EM structure of the beta2AR-mBRIL/1b3 Fab/Glue complex with ...

SupramoleculeName: Cryo-EM structure of the beta2AR-mBRIL/1b3 Fab/Glue complex with a partial agonist
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Beta-2 adrenergic receptor,Soluble cytochrome b562

MacromoleculeName: Beta-2 adrenergic receptor,Soluble cytochrome b562 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 51.594102 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKTIIALSYI FCLVFADYKD DDDKDEVWVV GMGIVMSLIV LAIVFGNVLV ITAIAKFERL QTVTNYFITS LACADLVMGL AVVPFGAAH ILMKMWTFGN FWCEFWTSID VLCVTASIET LCVIAVDRYF AITSPFKYQS LLTKNKARVI ILMVWIVSGL T SFLPIQMH ...String:
MKTIIALSYI FCLVFADYKD DDDKDEVWVV GMGIVMSLIV LAIVFGNVLV ITAIAKFERL QTVTNYFITS LACADLVMGL AVVPFGAAH ILMKMWTFGN FWCEFWTSID VLCVTASIET LCVIAVDRYF AITSPFKYQS LLTKNKARVI ILMVWIVSGL T SFLPIQMH WYRATHQEAI NCYAEETCCD FFTNQAYAIA SSIVSFYVPL VIMVFVYSRV FQEAKRQLAD LEDNWETLND NL KVIEKAD NAAQVKDALT KMRAAALDAQ KASGSGSPEM KDFRHGFDIL VGQIDDALKL ANEGKVKEAQ AAAEQLKTTR NAY IQKYLK FCLKEHKALK TLGIIMGTFT LCWLPFFIVN IVHVIQDNLI RKEVYILLNW IGYVNSGFNP LIYSRSPDFR IAFQ ELLKI AALKEKIAAL KEKIAALKEA EEKRASRLEE ELRRRLTEGS HHHHHHHH

UniProtKB: Beta-2 adrenergic receptor, Soluble cytochrome b562, Beta-2 adrenergic receptor

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Macromolecule #2: ~{N}-[5-[(1~{R})-2-[[(2~{R})-1-(4-methoxyphenyl)propan-2-yl]amino...

MacromoleculeName: ~{N}-[5-[(1~{R})-2-[[(2~{R})-1-(4-methoxyphenyl)propan-2-yl]amino]-1-oxidanyl-ethyl]-2-oxidanyl-phenyl]methanamide
type: ligand / ID: 2 / Number of copies: 1 / Formula: H98
Molecular weightTheoretical: 344.405 Da
Chemical component information

ChemComp-H98:
~{N}-[5-[(1~{R})-2-[[(2~{R})-1-(4-methoxyphenyl)propan-2-yl]amino]-1-oxidanyl-ethyl]-2-oxidanyl-phenyl]methanamide / agonist*YM / Formoterol

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation statecell

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Sample preparation

BufferpH: 7.5
GridMaterial: NICKEL/TITANIUM
VitrificationCryogen name: NITROGEN

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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: 5.0 µm / Nominal defocus min: 1.2 µm
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 52.0 e/Å2
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: INSILICO MODEL
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 327890
FSC plot (resolution estimation)

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