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- EMDB-11927: Melanocortin receptor 4 (MC4R) Gs protein complex -

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Basic information

Entry
Database: EMDB / ID: EMD-11927
TitleMelanocortin receptor 4 (MC4R) Gs protein complex
Map data
SampleMelanocortine 4 (MC4R) - GalphaS protein comlex
  • (scFv16) x 2
  • (AMINOSERINE) x 2
  • Melanocortin receptor 4
  • (Guanine nucleotide-binding protein ...) x 3
  • (ligand) x 2
Function / homology
Function and homology information


melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / guanyl nucleotide binding / neuropeptide binding / diet induced thermogenesis / regulation of grooming behavior / energy reserve metabolic process / intrinsic component of membrane / hair follicle placode formation / feeding behavior ...melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / guanyl nucleotide binding / neuropeptide binding / diet induced thermogenesis / regulation of grooming behavior / energy reserve metabolic process / intrinsic component of membrane / hair follicle placode formation / feeding behavior / PKA activation in glucagon signalling / intracellular transport / Olfactory Signaling Pathway / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / regulation of metabolic process / G beta:gamma signalling through PLC beta / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / ADP signalling through P2Y purinoceptor 12 / G-protein activation / adenylate cyclase-activating adrenergic receptor signaling pathway / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Activation of G protein gated Potassium channels / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon signaling in metabolic regulation / cardiac muscle cell apoptotic process / G protein-coupled acetylcholine receptor signaling pathway / sensory perception of taste / developmental growth / positive regulation of cAMP-mediated signaling / sensory perception of smell / peptide hormone binding / G-protein beta/gamma-subunit complex / cellular response to catecholamine stimulus / G-protein gamma-subunit binding / G beta:gamma signalling through CDC42 / alkylglycerophosphoethanolamine phosphodiesterase activity / G alpha (z) signalling events / rhodopsin mediated signaling pathway / Glucagon-type ligand receptors / Hedgehog 'off' state / G beta:gamma signalling through BTK / adenylate cyclase-activating dopamine receptor signaling pathway / Vasopressin regulates renal water homeostasis via Aquaporins / photoreceptor outer segment membrane / photoreceptor disc membrane / positive regulation of potassium ion transmembrane transport / G-protein beta-subunit binding / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / bone development / G-protein beta/gamma-subunit complex binding / negative regulation of feeding behavior / cellular response to glucagon stimulus / renal water homeostasis / heterotrimeric G-protein complex / G beta:gamma signalling through PI3Kgamma / adenylate cyclase activator activity / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / G protein-coupled receptor activity / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / activation of adenylate cyclase activity / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / trans-Golgi network membrane / Wnt signaling pathway, calcium modulating pathway / cellular response to prostaglandin E stimulus / G alpha (12/13) signalling events / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating G protein-coupled receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / GTPase binding / retina development in camera-type eye / regulation of insulin secretion / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / photoreceptor inner segment / cognition / G alpha (s) signalling events / G alpha (i) signalling events / platelet aggregation / G alpha (q) signalling events / positive regulation of cold-induced thermogenesis / positive regulation of GTPase activity / positive regulation of bone resorption / cell population proliferation / cell body / lysosomal membrane / negative regulation of inflammatory response to antigenic stimulus / Extra-nuclear estrogen signaling / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / Ras protein signal transduction / platelet activation / protein folding / GTPase activity / synapse
Similarity search - Function
Melanocortin/ACTH receptor / Melanocortin receptor / Melanocortin 4 receptor / G-protein alpha subunit, group S / G-protein, gamma subunit / G-protein gamma subunit domain profile. / Guanine nucleotide-binding protein, beta subunit / G-protein gamma-like domain superfamily / G-protein, beta subunit / G-protein gamma-like domain ...Melanocortin/ACTH receptor / Melanocortin receptor / Melanocortin 4 receptor / G-protein alpha subunit, group S / G-protein, gamma subunit / G-protein gamma subunit domain profile. / Guanine nucleotide-binding protein, beta subunit / G-protein gamma-like domain superfamily / G-protein, beta subunit / G-protein gamma-like domain / G protein gamma subunit-like motifs / GGL domain / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G protein alpha subunit, helical insertion / G protein alpha subunit / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / GPCR, rhodopsin-like, 7TM / G protein-coupled receptor, rhodopsin-like / G-protein coupled receptors family 1 profile. / G-protein beta WD-40 repeat / WD40 repeat, conserved site / Trp-Asp (WD) repeats signature. / WD domain, G-beta repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain / 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
Guanine nucleotide-binding protein G(i) subunit alpha-1 / Melanocortin receptor 4 / 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) / Mus musculus (house mouse) / synthetic construct (others)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.97 Å
AuthorsDegtjarik O / Israeli H / Prabahar V / Shalev-Benami M
CitationJournal: Science / Year: 2021
Title: Structure reveals the activation mechanism of the MC4 receptor to initiate satiation signaling.
Authors: Hadar Israeli / Oksana Degtjarik / Fabrizio Fierro / Vidicha Chunilal / Amandeep Kaur Gill / Nicolas J Roth / Joaquin Botta / Vadivel Prabahar / Yoav Peleg / Li F Chan / Danny Ben-Zvi / ...Authors: Hadar Israeli / Oksana Degtjarik / Fabrizio Fierro / Vidicha Chunilal / Amandeep Kaur Gill / Nicolas J Roth / Joaquin Botta / Vadivel Prabahar / Yoav Peleg / Li F Chan / Danny Ben-Zvi / Peter J McCormick / Masha Y Niv / Moran Shalev-Benami /
Abstract: Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the ...Obesity is a global epidemic that causes morbidity and impaired quality of life. The melanocortin receptor 4 (MC4R) is at the crux of appetite, energy homeostasis, and body-weight control in the central nervous system and is a prime target for anti-obesity drugs. Here, we present the cryo-electron microscopy (cryo-EM) structure of the human MC4R-G signaling complex bound to the agonist setmelanotide, a cyclic peptide recently approved for the treatment of obesity. The work reveals the mechanism of MC4R activation, highlighting a molecular switch that initiates satiation signaling. In addition, our findings indicate that calcium (Ca) is required for agonist, but not antagonist, efficacy. These results fill a gap in the understanding of MC4R activation and could guide the design of future weight-management drugs.
History
DepositionNov 2, 2020-
Header (metadata) releaseApr 28, 2021-
Map releaseApr 28, 2021-
UpdateJun 2, 2021-
Current statusJun 2, 2021Processing site: PDBe / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7aue
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_11927.map.gz / Format: CCP4 / Size: 83.7 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.86 Å/pix.
x 280 pix.
= 240.8 Å
0.86 Å/pix.
x 280 pix.
= 240.8 Å
0.86 Å/pix.
x 280 pix.
= 240.8 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.86 Å
Density
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.03
Minimum - Maximum-0.08467538 - 0.13791774
Average (Standard dev.)5.6400386e-05 (±0.004564045)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions280280280
Spacing280280280
CellA=B=C: 240.8 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.860.860.86
M x/y/z280280280
origin x/y/z0.0000.0000.000
length x/y/z240.800240.800240.800
α/β/γ90.00090.00090.000
start NX/NY/NZ727265
NX/NY/NZ157157169
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS280280280
D min/max/mean-0.0850.1380.000

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Supplemental data

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Additional map: #1

Fileemd_11927_additional_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

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Sample components

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Entire Melanocortine 4 (MC4R) - GalphaS protein comlex

EntireName: Melanocortine 4 (MC4R) - GalphaS protein comlex / Number of components: 12

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Component #1: protein, Melanocortine 4 (MC4R) - GalphaS protein comlex

ProteinName: Melanocortine 4 (MC4R) - GalphaS protein comlex / Recombinant expression: No

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Component #2: protein, Melanocortine 4 (MC4R) - GalphaS protein comlex

ProteinName: Melanocortine 4 (MC4R) - GalphaS protein comlex / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, scFv16

ProteinName: scFv16 / Recombinant expression: No
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #4: protein, AMINOSERINE

ProteinName: AMINOSERINE / Recombinant expression: No
SourceSpecies: synthetic construct (others)

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Component #5: protein, Melanocortin receptor 4

ProteinName: Melanocortin receptor 4 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 38.972852 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #6: protein, Guanine nucleotide-binding protein G(i) subunit alpha-1,...

ProteinName: Guanine nucleotide-binding protein G(i) subunit alpha-1,Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 43.194902 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #7: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 39.286891 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #8: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 7.861143 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #9: protein, scFv16

ProteinName: scFv16 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 27.340482 kDa
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Trichoplusia ni (cabbage looper)

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Component #10: protein, AMINOSERINE

ProteinName: AMINOSERINE / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 1.121341 kDa
SourceSpecies: synthetic construct (others)

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Component #11: ligand, CALCIUM ION

LigandName: CALCIUM IONCalcium / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 4.007805 MDa

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Component #12: ligand, water

LigandName: water / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 1.801505 MDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionSpecimen conc.: 14 mg/mL / pH: 7.5
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Temperature: 295 K / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 45.5 e/Å2 / Illumination mode: OTHER
LensImaging mode: BRIGHT FIELD
Specimen HolderModel: OTHER
CameraDetector: OTHER

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 366496
3D reconstructionResolution: 2.97 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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