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- EMDB-37849: Cryo-EM structure of CB1-beta-arrestin1 complex -

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Entry
Database: EMDB / ID: EMD-37849
TitleCryo-EM structure of CB1-beta-arrestin1 complex
Map data
Sample
  • Complex: Cryo-EM structure of human cannabinoid receptor 1 with effector protein
    • Protein or peptide: Beta-arrestin-1
    • Protein or peptide: Fab30 heavy chain
    • Protein or peptide: Fab30 light chain
    • Protein or peptide: Cannabinoid receptor 1,Vasopressin V2 receptor
  • Ligand: methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate
Keywordscannabinoid receptor / arrestin / biased signal / class A GPCR / MEMBRANE PROTEIN
Function / homology
Function and homology information


TGFBR3 regulates TGF-beta signaling / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / MAP2K and MAPK activation / Activation of SMO / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / cannabinoid signaling pathway / regulation of penile erection ...TGFBR3 regulates TGF-beta signaling / renal water retention / Defective AVP does not bind AVPR2 and causes neurohypophyseal diabetes insipidus (NDI) / MAP2K and MAPK activation / Activation of SMO / Vasopressin-like receptors / regulation of systemic arterial blood pressure by vasopressin / vasopressin receptor activity / cannabinoid signaling pathway / regulation of penile erection / Golgi Associated Vesicle Biogenesis / Lysosome Vesicle Biogenesis / negative regulation of dopamine secretion / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / negative regulation of mast cell activation / AP-2 adaptor complex binding / Ub-specific processing proteases / negative regulation of fatty acid beta-oxidation / clathrin coat of coated pit / clathrin heavy chain binding / negative regulation of serotonin secretion / positive regulation of acute inflammatory response to antigenic stimulus / regulation of feeding behavior / Cargo recognition for clathrin-mediated endocytosis / hemostasis / desensitization of G protein-coupled receptor signaling pathway / telencephalon development / regulation of presynaptic cytosolic calcium ion concentration / negative regulation of action potential / Clathrin-mediated endocytosis / clathrin-dependent endocytosis / positive regulation of blood pressure / positive regulation of fever generation / Class A/1 (Rhodopsin-like receptors) / G protein-coupled receptor internalization / acetylcholine receptor binding / inositol hexakisphosphate binding / axonal fasciculation / regulation of metabolic process / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (s) signalling events / clathrin binding / regulation of synaptic transmission, GABAergic / small molecule binding / positive regulation of systemic arterial blood pressure / pseudopodium / phosphatidylinositol-3,4,5-trisphosphate binding / positive regulation of intracellular signal transduction / positive regulation of receptor internalization / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / endocytic vesicle / negative regulation of Notch signaling pathway / maternal process involved in female pregnancy / cellular response to hormone stimulus / regulation of synaptic transmission, glutamatergic / activation of adenylate cyclase activity / negative regulation of blood pressure / positive regulation of vasoconstriction / response to nutrient / response to cytokine / regulation of insulin secretion / GABA-ergic synapse / response to nicotine / response to cocaine / G protein-coupled receptor binding / clathrin-coated endocytic vesicle membrane / G protein-coupled receptor activity / positive regulation of neuron projection development / receptor internalization / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / memory / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Vasopressin regulates renal water homeostasis via Aquaporins / glucose homeostasis / protein transport / Cargo recognition for clathrin-mediated endocytosis / actin cytoskeleton / Clathrin-mediated endocytosis / positive regulation of protein phosphorylation / presynaptic membrane / growth cone / ubiquitin-dependent protein catabolic process / cytoplasmic vesicle / G alpha (i) signalling events / G alpha (s) signalling events / spermatogenesis / molecular adaptor activity / response to lipopolysaccharide / response to ethanol / mitochondrial outer membrane / positive regulation of ERK1 and ERK2 cascade / endosome / G protein-coupled receptor signaling pathway / positive regulation of apoptotic process / membrane raft / negative regulation of cell population proliferation / positive regulation of cell population proliferation / positive regulation of gene expression / perinuclear region of cytoplasm
Similarity search - Function
Vasopressin V2 receptor / Vasopressin receptor / Cannabinoid receptor type 1 / Cannabinoid receptor family / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain ...Vasopressin V2 receptor / Vasopressin receptor / Cannabinoid receptor type 1 / Cannabinoid receptor family / Arrestin, conserved site / Arrestins signature. / Arrestin / Arrestin, N-terminal / Arrestin-like, N-terminal / Arrestin C-terminal-like domain / Arrestin (or S-antigen), N-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin (or S-antigen), C-terminal domain / Arrestin-like, C-terminal / 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) / Immunoglobulin E-set
Similarity search - Domain/homology
Beta-arrestin-1 / Cannabinoid receptor 1 / Vasopressin V2 receptor
Similarity search - Component
Biological speciesBos taurus (domestic cattle) / Homo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.2 Å
AuthorsLiao Y / Zhang H / Shen Q / Cai C
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Cell / Year: 2023
Title: Snapshot of the cannabinoid receptor 1-arrestin complex unravels the biased signaling mechanism.
Authors: Yu-Ying Liao / Huibing Zhang / Qingya Shen / Chenxi Cai / Yu Ding / Dan-Dan Shen / Jia Guo / Jiao Qin / Yingjun Dong / Yan Zhang / Xiao-Ming Li /
Abstract: Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits, along with adverse effects, via G and β-arrestin signaling pathways. However, the lack ...Cannabis activates the cannabinoid receptor 1 (CB1), which elicits analgesic and emotion regulation benefits, along with adverse effects, via G and β-arrestin signaling pathways. However, the lack of understanding of the mechanism of β-arrestin-1 (βarr1) coupling and signaling bias has hindered drug development targeting CB1. Here, we present the high-resolution cryo-electron microscopy structure of CB1-βarr1 complex bound to the synthetic cannabinoid MDMB-Fubinaca (FUB), revealing notable differences in the transducer pocket and ligand-binding site compared with the G protein complex. βarr1 occupies a wider transducer pocket promoting substantial outward movement of the TM6 and distinctive twin toggle switch rearrangements, whereas FUB adopts a different pose, inserting more deeply than the G-coupled state, suggesting the allosteric correlation between the orthosteric binding pocket and the partner protein site. Taken together, our findings unravel the molecular mechanism of signaling bias toward CB1, facilitating the development of CB1 agonists.
History
DepositionOct 19, 2023-
Header (metadata) releaseMar 20, 2024-
Map releaseMar 20, 2024-
UpdateOct 16, 2024-
Current statusOct 16, 2024Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_37849.png

Downloads & links

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Map

FileDownload / File: emd_37849.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

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AxesZ (Sec.)Y (Row.)X (Col.)
0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å		0.93 Å/pix.
x 256 pix.
= 238.08 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.93 Å
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Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.0035
Minimum - Maximum-0.025322681 - 0.046268616
Average (Standard dev.)0.000000027926436 (±0.0009535786)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 238.08 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_37849_half_map_1.map
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Half map: #1

Fileemd_37849_half_map_2.map
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Sample components

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Entire : Cryo-EM structure of human cannabinoid receptor 1 with effector p...

EntireName: Cryo-EM structure of human cannabinoid receptor 1 with effector protein
Components
  • Complex: Cryo-EM structure of human cannabinoid receptor 1 with effector protein
    • Protein or peptide: Beta-arrestin-1
    • Protein or peptide: Fab30 heavy chain
    • Protein or peptide: Fab30 light chain
    • Protein or peptide: Cannabinoid receptor 1,Vasopressin V2 receptor
  • Ligand: methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate

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Supramolecule #1: Cryo-EM structure of human cannabinoid receptor 1 with effector p...

SupramoleculeName: Cryo-EM structure of human cannabinoid receptor 1 with effector protein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Details: MDMB-Fubinaca, cannabinoid receptor 1, arrestin2, Fab30
Source (natural)Organism: Bos taurus (domestic cattle)

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Macromolecule #1: Beta-arrestin-1

MacromoleculeName: Beta-arrestin-1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 44.135273 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVEPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA CGVDYEVKAF CAENLEEKIH K RNSVRLVI ...String:
MGDKGTRVFK KASPNGKLTV YLGKRDFVDH IDLVEPVDGV VLVDPEYLKE RRVYVTLTCA FRYGREDLDV LGLTFRKDLF VANVQSFPP APEDKKPLTR LQERLIKKLG EHAYPFTFEI PPNLPCSVTL QPGPEDTGKA CGVDYEVKAF CAENLEEKIH K RNSVRLVI EKVQYAPERP GPQPTAETTR QFLMSDKPLH LEASLDKEIY YHGEPISVNV HVTNNTNKTV KKIKISVRQY AD ICLFNTA QYKCPVAMEE ADDTVAPSST FCKVYTLTPF LANNREKRGL ALDGKLKHED TNLASSTLLR EGANREILGI IVS YKVKVK LVVSRGGLLG DLASSDVAVE LPFTLMHPKP KEEPPHREVP EHETPVDTNL IELDTNDDDA AAEDFAR

UniProtKB: Beta-arrestin-1

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Macromolecule #2: Fab30 heavy chain

MacromoleculeName: Fab30 heavy chain / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.650502 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: EISEVQLVES GGGLVQPGGS LRLSCAASGF NVYSSSIHWV RQAPGKGLEW VASISSYYGY TYYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARSRQFWYSG LDYWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA ...String:
EISEVQLVES GGGLVQPGGS LRLSCAASGF NVYSSSIHWV RQAPGKGLEW VASISSYYGY TYYADSVKGR FTISADTSKN TAYLQMNSL RAEDTAVYYC ARSRQFWYSG LDYWGQGTLV TVSSASTKGP SVFPLAPSSK STSGGTAALG CLVKDYFPEP V TVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSS LGTQTYICNV NHKPSNTKVD KKVEPKSCDK THHHHHHHHH

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Macromolecule #3: Fab30 light chain

MacromoleculeName: Fab30 light chain / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 23.435064 KDa
Recombinant expressionOrganism: Escherichia coli BL21(DE3) (bacteria)
SequenceString: SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYKYVPVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD ...String:
SDIQMTQSPS SLSASVGDRV TITCRASQSV SSAVAWYQQK PGKAPKLLIY SASSLYSGVP SRFSGSRSGT DFTLTISSLQ PEDFATYYC QQYKYVPVTF GQGTKVEIKR TVAAPSVFIF PPSDSQLKSG TASVVCLLNN FYPREAKVQW KVDNALQSGN S QESVTEQD SKDSTYSLSS TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC

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Macromolecule #4: Cannabinoid receptor 1,Vasopressin V2 receptor

MacromoleculeName: Cannabinoid receptor 1,Vasopressin V2 receptor / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 50.310129 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL TSFRGSPFQE KMTAGDNPQL VPADQVNITE FYNKSLSSF KENEENIQCG ENFMDIECFM VLNPSQQLAI AVLSLTLGTF TVLENLLVLC VILHSRSLRC RPSYHFIGSL A VADLLGSV ...String:
MKSILDGLAD TTFRTITTDL LYVGSNDIQY EDIKGDMASK LGYFPQKFPL TSFRGSPFQE KMTAGDNPQL VPADQVNITE FYNKSLSSF KENEENIQCG ENFMDIECFM VLNPSQQLAI AVLSLTLGTF TVLENLLVLC VILHSRSLRC RPSYHFIGSL A VADLLGSV IFVYSFIDFH VFHRKDSRNV FLFKLGGVTA SFTASVGSLF LTAIDRYISI HRPLAYKRIV TRPKAVVAFC LM WTIAIVI AVLPLLGWNC EKLQSVCSDI FPHIDETYLM FWIGVTSVLL LFIVYAYMYI LWKAHSHAVR MIQRGTQKSI IIH TSEDGK VQVTRPDQAR MDIRLAKTLV LILVVLIICW GPLLAIMVYD VFGKMNKLIK TVFAFCSMLC LLNSTVNPII YALR SKDLR HAFRSMFPCA RGRTPPSLGP QDE(SEP)C(TPO)(TPO)A(SEP)(SEP) (SEP)LAKDTSS

UniProtKB: Cannabinoid receptor 1, Vasopressin V2 receptor

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Macromolecule #5: methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-me...

MacromoleculeName: methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate
type: ligand / ID: 5 / Number of copies: 1 / Formula: KCA
Molecular weightTheoretical: 397.443 Da
Chemical component information

ChemComp-KCA:
methyl N-{1-[(4-fluorophenyl)methyl]-1H-indazole-3-carbonyl}-3-methyl-L-valinate / agonist*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

Concentration5 mg/mL
BufferpH: 7.5
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 52.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 5.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.2 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 110196
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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