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- EMDB-36951: Cannabinoid Receptor 1 bound to Fenofibrate coupling MiniGsq and ... -

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Basic information

Entry
Database: EMDB / ID: EMD-36951
TitleCannabinoid Receptor 1 bound to Fenofibrate coupling MiniGsq and Nb35 Complex
Map data
Sample
  • Complex: Cannabinoid Receptor 1-G protein complex
    • Protein or peptide: Soluble cytochrome b562,Cannabinoid receptor 1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35
  • Ligand: Fenofibrate
KeywordsGPCR / MEMBRANE PROTEIN
Function / homology
Function and homology information


cannabinoid signaling pathway / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / regulation of presynaptic cytosolic calcium ion concentration / Class A/1 (Rhodopsin-like receptors) / axonal fasciculation / regulation of metabolic process / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation ...cannabinoid signaling pathway / retrograde trans-synaptic signaling by endocannabinoid / cannabinoid receptor activity / regulation of presynaptic cytosolic calcium ion concentration / Class A/1 (Rhodopsin-like receptors) / axonal fasciculation / regulation of metabolic process / PKA activation in glucagon signalling / developmental growth / hair follicle placode formation / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / D1 dopamine receptor binding / intracellular transport / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / cellular response to glucagon stimulus / regulation of insulin secretion / adenylate cyclase activator activity / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / electron transport chain / G protein-coupled receptor activity / bone development / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / platelet aggregation / G-protein beta/gamma-subunit complex binding / cognition / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / sensory perception of smell / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / glucose homeostasis / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / actin cytoskeleton / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cold-induced thermogenesis / retina development in camera-type eye / G protein activity / presynaptic membrane / growth cone / GTPase binding / Ca2+ pathway / fibroblast proliferation / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / mitochondrial outer membrane / periplasmic space / electron transfer activity / Extra-nuclear estrogen signaling / cell population proliferation / G protein-coupled receptor signaling pathway / membrane raft / iron ion binding / lysosomal membrane / GTPase activity / heme binding / synapse
Similarity search - Function
Cannabinoid receptor type 1 / Cannabinoid receptor family / G-protein alpha subunit, group S / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit ...Cannabinoid receptor type 1 / Cannabinoid receptor family / G-protein alpha subunit, group S / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / Serpentine type 7TM GPCR chemoreceptor Srsx / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G-alpha domain profile. / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / 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) / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Soluble cytochrome b562 / Cannabinoid receptor 1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.88 Å
AuthorsTang WQ / Wang TX / Li FH / Wang JY
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Adv Sci (Weinh) / Year: 2024
Title: Fenofibrate Recognition and G Protein Coupling Mechanisms of the Human Cannabinoid Receptor CB1.
Authors: Tianxin Wang / Wenqin Tang / Ziyi Zhao / Ran Zhao / Zhenyu Lv / Xuzhen Guo / Quanchang Gu / Boxiang Liu / Haoyu Lv / Jiayan Chen / Kaiquan Zhang / Fahui Li / Jiangyun Wang /
Abstract: The G-protein-coupled human cannabinoid receptor 1 (CB1) is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. The structures of CB1-G complexes ...The G-protein-coupled human cannabinoid receptor 1 (CB1) is a promising therapeutic target for pain management, inflammation, obesity, and substance abuse disorders. The structures of CB1-G complexes in synthetic agonist-bound forms have been resolved to date. However, the commercial drug recognition and G coupling mechanisms of CB1 remain elusive. Herein, the cryo-electron microscopy (cryo-EM) structure of CB1-G complex, in fenofibrate-bound form, at near-atomic resolution, is reported. The structure elucidates the delicate mechanisms of the precise fenofibrate recognition and G protein coupling by CB1 and will facilitate future drug discovery and design.
History
DepositionJul 30, 2023-
Header (metadata) releaseFeb 14, 2024-
Map releaseFeb 14, 2024-
UpdateJul 23, 2025-
Current statusJul 23, 2025Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_36951.png

Downloads & links

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Map

FileDownload / File: emd_36951.map.gz / Format: CCP4 / Size: 125 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesX (Sec.)Y (Row.)Z (Col.)
0.83 Å/pix.
x 320 pix.
= 266.24 Å		0.83 Å/pix.
x 320 pix.
= 266.24 Å		0.83 Å/pix.
x 320 pix.
= 266.24 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.832 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 5.0
Minimum - Maximum-35.003407000000003 - 53.766599999999997
Average (Standard dev.)0.002005507 (±1.02972)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderZYX
Origin000
Dimensions320320320
Spacing320320320
CellA=B=C: 266.24 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Cannabinoid Receptor 1-G protein complex

EntireName: Cannabinoid Receptor 1-G protein complex
Components
  • Complex: Cannabinoid Receptor 1-G protein complex
    • Protein or peptide: Soluble cytochrome b562,Cannabinoid receptor 1
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nanobody 35
  • Ligand: Fenofibrate

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Supramolecule #1: Cannabinoid Receptor 1-G protein complex

SupramoleculeName: Cannabinoid Receptor 1-G protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #5, #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 30.652561 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString: MGHHHHHHEN LYFQGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGADN SGKSTIVKQM RILHGGSGGS GGTSGIFET KFQVDKVNFH MFDVGGQRDE RRKWIQCFND VTAIIFVVDS SDYNRLQEAL NLFKSIWNNR WLRTISVILF L NKQDLLAE ...String:
MGHHHHHHEN LYFQGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGADN SGKSTIVKQM RILHGGSGGS GGTSGIFET KFQVDKVNFH MFDVGGQRDE RRKWIQCFND VTAIIFVVDS SDYNRLQEAL NLFKSIWNNR WLRTISVILF L NKQDLLAE KVLAGKSKIE DYFPEFARYT TPEDATPEPG EDPRVTRAKY FIRDEFLRIS TASGDGRHYC YPHFTCAVDT EN ARRIFND CKDIILQMNL REYNLV

UniProtKB: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short, Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

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Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.41693 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL ...String:
MSELDQLRQE AEQLKNQIRD ARKACADATL SQITNNIDPV GRIQMRTRRT LRGHLAKIYA MHWGTDSRLL VSASQDGKLI IWDSYTTNK VHAIPLRSSW VMTCAYAPSG NYVACGGLDN ICSIYNLKTR EGNVRVSREL AGHTGYLSCC RFLDDNQIVT S SGDTTCAL WDIETGQQTT TFTGHTGDVM SLSLAPDTRL FVSGACDASA KLWDVREGMC RQTFTGHESD INAICFFPNG NA FATGSDD ATCRLFDLRA DQELMTYSHD NIICGITSVS FSKSGRLLLA GYDDFNCNVW DALKADRAGV LAGHDNRVSC LGV TDDGMA VATGSWDSFL KIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.49796 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MHHHHHHGGG SDSLEFIASK LAGGGSMASN NTASIAQARK LVEQLKMEAN IDRIKVSKAA ADLMAYCEAH AKEDPLLTPV PASENPFRE KKFFSAIL

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

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Macromolecule #4: Nanobody 35

MacromoleculeName: Nanobody 35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 15.271938 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
MQVQLQESGG GLVQPGGSLR LSCAASGFTF SNYKMNWVRQ APGKGLEWVS DISQSGASIS YTGSVKGRFT ISRDNAKNTL YLQMNSLKP EDTAVYYCAR CPAPFTRDCF DVTSTTYAYR GQGTQVTVSS HHHHHHEPEA

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Macromolecule #5: Soluble cytochrome b562,Cannabinoid receptor 1

MacromoleculeName: Soluble cytochrome b562,Cannabinoid receptor 1 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 59.685355 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGGRA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLLEVL F QGPVPADQ ...String:
MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGGRA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLLEVL F QGPVPADQ VNITEFYNKS LSSFKENEEN IQCGENFMDI ECFMVLNPSQ QLAIAVLSLT LGTFTVLENL LVLCVILHSR SL RCRPSYH FIGSLAVADL LGSVIFVYSF IDFHVFHRKD SRNVFLFKLG GVTASFTASV GSLFLIAIDR YISIHRPLAY KRI VTRPKA VVAFCLMWTI AIVIAVLPLL GWNCEKLQSV CSDIFPHIDK TYLMFWIGVV SVLLLFIVYA YMYILWKAHS HAVR MIQRG TQKSIIIHTS EDGKVQVTRP DQARMDIELA KTLVLILVVL IICWGPLLAI MVYDVFGKMN KLIKTVFAFC SMLCL LNST VNPIIYALRS KDLRHAFRSM FPSCEGTAQP LDNSHHHHHH H

UniProtKB: Soluble cytochrome b562, Cannabinoid receptor 1

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Macromolecule #6: Fenofibrate

MacromoleculeName: Fenofibrate / type: ligand / ID: 6 / Number of copies: 1 / Formula: J3O
Molecular weightTheoretical: 360.831 Da

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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: 60.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6kpg

Final reconstructionResolution.type: BY AUTHOR / Resolution: 2.88 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 352452
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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