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- EMDB-31500: ghrelin-bound ghrelin receptor in complex with Gq -

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Basic information

Entry
Database: EMDB / ID: EMD-31500
Titleghrelin-bound ghrelin receptor in complex with Gq
Map data
Sample
  • Complex: ghrelin-bound ghrelin receptor in complex with Gq
    • Protein or peptide: Engineered G-alpha-q subunit
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Ghrelin-28
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: NB35
    • Protein or peptide: Soluble cytochrome b562
  • Ligand: OCTANOIC ACID (CAPRYLIC ACID)
  • Ligand: CHOLESTEROL
Keywordsghrelin / GPCR / Gq / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of bone development / positive regulation of gastric mucosal blood circulation / ghrelin receptor binding / negative regulation of locomotion / cortisol secretion / growth hormone-releasing hormone activity / negative regulation of circadian sleep/wake cycle, REM sleep / positive regulation of small intestinal transit / regulation of response to food / regulation of gastric motility ...positive regulation of bone development / positive regulation of gastric mucosal blood circulation / ghrelin receptor binding / negative regulation of locomotion / cortisol secretion / growth hormone-releasing hormone activity / negative regulation of circadian sleep/wake cycle, REM sleep / positive regulation of small intestinal transit / regulation of response to food / regulation of gastric motility / regulation of transmission of nerve impulse / positive regulation of circadian sleep/wake cycle, non-REM sleep / positive regulation of cortisol secretion / positive regulation of corticotropin secretion / positive regulation of growth rate / gastric acid secretion / positive regulation of appetite / growth hormone secretion / positive regulation of small intestine smooth muscle contraction / neuronal dense core vesicle lumen / positive regulation of eating behavior / adult feeding behavior / positive regulation of growth hormone secretion / positive regulation of growth hormone receptor signaling pathway / actin polymerization or depolymerization / positive regulation of multicellular organism growth / cartilage development / regulation of postsynapse organization / positive regulation of synapse assembly / positive regulation of vascular endothelial cell proliferation / negative regulation of interleukin-1 beta production / positive regulation of sprouting angiogenesis / negative regulation of endothelial cell proliferation / dendrite development / negative regulation of interleukin-6 production / decidualization / protein tyrosine kinase activator activity / negative regulation of tumor necrosis factor production / response to electrical stimulus / Synthesis, secretion, and deacylation of Ghrelin / positive regulation of insulin secretion involved in cellular response to glucose stimulus / postsynaptic modulation of chemical synaptic transmission / synapse assembly / response to hormone / hormone-mediated signaling pathway / positive regulation of adipose tissue development / negative regulation of angiogenesis / Peptide ligand-binding receptors / excitatory postsynaptic potential / negative regulation of insulin secretion / G protein-coupled receptor binding / positive regulation of insulin secretion / negative regulation of inflammatory response / Schaffer collateral - CA1 synapse / response to estrogen / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / glucose metabolic process / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / 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 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / cellular response to catecholamine stimulus / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / adenylate cyclase-activating dopamine receptor signaling pathway / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / regulation of cell population proliferation / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cold-induced thermogenesis / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / GTPase binding / Ca2+ pathway
Similarity search - Function
Preproghrelin peptide / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Motilin/ghrelin-associated peptide / Motilin/ghrelin / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain ...Preproghrelin peptide / Motilin/ghrelin-associated peptide / Motilin/ghrelin / Motilin/ghrelin-associated peptide / Motilin/ghrelin / 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 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
Similarity search - Domain/homology
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 / Appetite-regulating hormone
Similarity search - Component
Biological speciesHomo sapiens (human) / Lama glama (llama)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsWang Y / Zhuang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31770796 China
CitationJournal: Nat Commun / Year: 2021
Title: Molecular recognition of an acyl-peptide hormone and activation of ghrelin receptor.
Authors: Yue Wang / Shimeng Guo / Youwen Zhuang / Ying Yun / Peiyu Xu / Xinheng He / Jia Guo / Wanchao Yin / H Eric Xu / Xin Xie / Yi Jiang /
Abstract: Ghrelin, also called "the hunger hormone", is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature ...Ghrelin, also called "the hunger hormone", is a gastric peptide hormone that regulates food intake, body weight, as well as taste sensation, reward, cognition, learning and memory. One unique feature of ghrelin is its acylation, primarily with an octanoic acid, which is essential for its binding and activation of the ghrelin receptor, a G protein-coupled receptor. The multifaceted roles of ghrelin make ghrelin receptor a highly attractive drug target for growth retardation, obesity, and metabolic disorders. Here we present two cryo-electron microscopy structures of G-coupled ghrelin receptor bound to ghrelin and a synthetic agonist, GHRP-6. Analysis of these two structures reveals a unique binding pocket for the octanoyl group, which guides the correct positioning of the peptide to initiate the receptor activation. Together with mutational and functional data, our structures define the rules for recognition of the acylated peptide hormone and activation of ghrelin receptor, and provide structural templates to facilitate drug design targeting ghrelin receptor.
History
DepositionJul 5, 2021-
Header (metadata) releaseAug 18, 2021-
Map releaseAug 18, 2021-
UpdateOct 30, 2024-
Current statusOct 30, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.13
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.13
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7f9y
  • Surface level: 0.13
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31500.png

Downloads & links

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Map

FileDownload / File: emd_31500.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.07 Å/pix.
x 200 pix.
= 214.2 Å		1.07 Å/pix.
x 200 pix.
= 214.2 Å		1.07 Å/pix.
x 200 pix.
= 214.2 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.071 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.13 / Movie #1: 0.13
Minimum - Maximum-0.060596265 - 1.9031589
Average (Standard dev.)0.0018974739 (±0.03308573)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 214.2 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0711.0711.071
M x/y/z200200200
origin x/y/z0.0000.0000.000
length x/y/z214.200214.200214.200
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ112112112
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS200200200
D min/max/mean-0.0611.9030.002

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Supplemental data

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Sample components

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Entire : ghrelin-bound ghrelin receptor in complex with Gq

EntireName: ghrelin-bound ghrelin receptor in complex with Gq
Components
  • Complex: ghrelin-bound ghrelin receptor in complex with Gq
    • Protein or peptide: Engineered G-alpha-q subunit
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Ghrelin-28
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: NB35
    • Protein or peptide: Soluble cytochrome b562
  • Ligand: OCTANOIC ACID (CAPRYLIC ACID)
  • Ligand: CHOLESTEROL

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Supramolecule #1: ghrelin-bound ghrelin receptor in complex with Gq

SupramoleculeName: ghrelin-bound ghrelin receptor in complex with Gq / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Engineered G-alpha-q subunit

MacromoleculeName: Engineered G-alpha-q subunit / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.855578 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MMGCTLSAED KAAVERSKMI EKQLQKDKQV YRRTLRLLLL GADNSGKSTI VKQMRIYHVN GYSEEECKQY KAVVYSNTIQ SIIAIIRAM GRLKIDFGDS ARADDARQLF VLAGAAEEGF MTAELAGVIK RLWKDSGVQA CFNRSREYQL NDSAAYYLND L DRIAQPNY ...String:
MMGCTLSAED KAAVERSKMI EKQLQKDKQV YRRTLRLLLL GADNSGKSTI VKQMRIYHVN GYSEEECKQY KAVVYSNTIQ SIIAIIRAM GRLKIDFGDS ARADDARQLF VLAGAAEEGF MTAELAGVIK RLWKDSGVQA CFNRSREYQL NDSAAYYLND L DRIAQPNY IPTQQDVLRT RVKTSGIFET KFQVDKVNFH MFDVGAQRDE RRKWIQCFND VTAIIFVVDS SDYNRLQEAL ND FKSIWNN RWLRTISVIL FLNKQDLLAE KVLAGKSKIE DYFPEFARYT TPEDATPEPG EDPRVTRAKY FIRKEFVDIS TAS GDGRHI CYPHFTCSVD TENARRIFND CKDIILQMNL REYNLV

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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: 40.226992 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String:
MGSLLQSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWNG SSGGGGSGGG GSSGVSGWRL FKKIS

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

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Macromolecule #3: Ghrelin-28

MacromoleculeName: Ghrelin-28 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 3.252726 KDa
Recombinant expressionOrganism: Homo sapiens (human)
SequenceString:
GSSFLSPEHQ RVQQRKESKK PPAKLQPR

UniProtKB: Appetite-regulating hormone

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Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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

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Macromolecule #5: NB35

MacromoleculeName: NB35 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Lama glama (llama)
Molecular weightTheoretical: 15.343019 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
MAQVQLQESG GGLVQPGGSL RLSCAASGFT FSNYKMNWVR QAPGKGLEWV SDISQSGASI SYTGSVKGRF TISRDNAKNT LYLQMNSLK PEDTAVYYCA RCPAPFTRDC FDVTSTTYAY RGQGTQVTVS SHHHHHHEPE A

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Macromolecule #6: Soluble cytochrome b562

MacromoleculeName: Soluble cytochrome b562 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 74.282609 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MKTIIALSYI FCLVFAHHHH HHHHHHADLE DNWETLNDNL KVIEKADNAA QVKDALTKMR AAALDAQKAT PPKLEDKSPD SPEMKDFRH GFDILVGQID DALKLANEGK VKEAQAAAEQ LKTTRNAYIQ KYLMWNATPS EEPGFNLTLA DLDWDASPGN D SLGDELLQ ...String:
MKTIIALSYI FCLVFAHHHH HHHHHHADLE DNWETLNDNL KVIEKADNAA QVKDALTKMR AAALDAQKAT PPKLEDKSPD SPEMKDFRH GFDILVGQID DALKLANEGK VKEAQAAAEQ LKTTRNAYIQ KYLMWNATPS EEPGFNLTLA DLDWDASPGN D SLGDELLQ LFPAPLLAGV TATCVALFVV GIAGNLLTML VVSRFRELRT TTNLYLSSMA FSDLLIFLCM PLDLVRLWQY RP WNFGDLL CKLFQFVSES CTYATVLTIT ALSVERYFAI CFPLRAKVVV TKGRVKLVIF VIWAVAFCSA GPIFVLVGVE HEN GTDPWD TNECRPTEFA VRSGLLTVMV WVSSIFFFLP VFCLTVLYSL IGRKLWRRRR GDAVVGASLR DQNHKQTVKM LAVV VFAFI LCWLPFHVGR YLFSKSFEPG SLEIAQISQY CNLVSFVLFY LSAAINPILY NIMSKKYRVA VFRLLGFEPF SQRKL STLK DESSRAWTES SINTGSAGSV FTLEDFVGDW EQTAAYNLDQ VLEQGGVSSL LQNLAVSVTP IQRIVRSGEN ALKIDI HVI IPYEGLSADQ MAQIEEVFKV VYPVDDHHFK VILPYGTLVI DGVTPNMLNY FGRPYEGIAV FDGKKITVTG TLWNGNK II DERLITPDGS MLFRVTINS

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Macromolecule #7: OCTANOIC ACID (CAPRYLIC ACID)

MacromoleculeName: OCTANOIC ACID (CAPRYLIC ACID) / type: ligand / ID: 7 / Number of copies: 1 / Formula: OCA
Molecular weightTheoretical: 144.211 Da
Chemical component information

ChemComp-OCA:
OCTANOIC ACID (CAPRYLIC ACID)

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Macromolecule #8: CHOLESTEROL

MacromoleculeName: CHOLESTEROL / type: ligand / ID: 8 / Number of copies: 2 / Formula: CLR
Molecular weightTheoretical: 386.654 Da
Chemical component information

ChemComp-CLR:
CHOLESTEROL

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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: 7.4
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: 80.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 3.0 µm / Nominal defocus min: 0.5 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: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 522055
Initial angle assignmentType: RANDOM ASSIGNMENT
Final angle assignmentType: MAXIMUM LIKELIHOOD

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