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- EMDB-67804: Cryo-EM structure of the setmelanotide-bound human melanocortin r... -

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Entry
Database: EMDB / ID: EMD-67804
TitleCryo-EM structure of the setmelanotide-bound human melanocortin receptor 4 (MC4R)-Gq complex
Map data
Sample
  • Complex: Cryo-EM structure of setmelanotide-bound human melanocortin receptor 4 in complex with Gq protein
    • Protein or peptide: Setmelanotide
    • Protein or peptide: Melanocortin receptor 4,LgBiT subunit
    • Protein or peptide: G subunit q (Gi1-Gq chimeric)
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,HiBiT
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Ligand: CALCIUM ION
Keywordshuman melanocortin receptor 4 / G protein-coupled receptor / setmelanotide / Gq / MEMBRANE PROTEIN
Function / homology
Function and homology information


response to melanocyte-stimulating hormone / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / corticotropin receptor activity / regulation of feeding behavior / non-motile cilium membrane / negative regulation of appetite / feeding behavior / positive regulation of bone resorption / G-protein activation ...response to melanocyte-stimulating hormone / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / corticotropin receptor activity / regulation of feeding behavior / non-motile cilium membrane / negative regulation of appetite / feeding behavior / positive regulation of bone resorption / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / neuropeptide binding / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through PLC beta / ADP signalling through P2Y purinoceptor 1 / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through CDC42 / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G alpha (12/13) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Ca2+ pathway / G alpha (z) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / Extra-nuclear estrogen signaling / G alpha (q) signalling events / G alpha (s) signalling events / negative regulation of feeding behavior / photoreceptor outer segment membrane / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / spectrin binding / G alpha (i) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / sensory perception of taste / alkylglycerophosphoethanolamine phosphodiesterase activity / retina development in camera-type eye / cardiac muscle cell apoptotic process / photoreceptor outer segment / regulation of eating behavior / Transcriptional and post-translational regulation of MITF-M expression and activity / photoreceptor inner segment / Peptide ligand-binding receptors / cell population proliferation / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cellular response to catecholamine stimulus / adenylate cyclase-activating dopamine receptor signaling pathway / heterotrimeric G-protein complex / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / positive regulation of cytosolic calcium ion concentration / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / GTPase binding / cell body / cellular response to hypoxia / G alpha (s) signalling events / G protein-coupled receptor signaling pathway / ubiquitin protein ligase binding / GTPase activity / dendrite / synapse / protein-containing complex binding / membrane / plasma membrane / cytoplasm
Similarity search - Function
Melanocortin 4 receptor / Melanocortin receptor 3-5 / Melanocortin/ACTH receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 ...Melanocortin 4 receptor / Melanocortin receptor 3-5 / Melanocortin/ACTH receptor / Serpentine type 7TM GPCR chemoreceptor Srsx / 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 / Guanine nucleotide-binding protein, beta subunit / G protein beta WD-40 repeat protein / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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
Melanocortin receptor 4 / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Similarity search - Component
Biological speciesHomo sapiens (human) / synthetic construct (others) / Bos taurus (domestic cattle)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.11 Å
AuthorsFeng WB / Zhou QT / Wang MW
Funding support China, 6 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)82273961 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)81872915 China
Other government2021ZD0203400 China
Other governmentZDKJ2021028 China
Other government2024M762003 China
CitationJournal: Acta Pharm Sin B / Year: 2026
Title: Rationale of renewed efforts in developing MC4R modulators to treat metabolic disorders.
Authors: Wenbo Feng / Qingtong Zhou / Ming-Wei Wang /
Abstract: The melanocortin-4 receptor (MC4R) is a key regulator of energy balance and a potential target for weight management. Early drug discovery endeavors were hindered by incomplete understanding of its ...The melanocortin-4 receptor (MC4R) is a key regulator of energy balance and a potential target for weight management. Early drug discovery endeavors were hindered by incomplete understanding of its signal transduction mechanisms and broad activation of G pathways. Recent advances indicate that MC4R elicits multiple intracellular responses, with G signaling in the paraventricular nucleus (PVN) neurons playing a central role in appetite suppression. High-resolution cryo-electron microscopy structures of MC4R, such as the setmelanotide-MC4R-G complex reported here, provide valuable insights into ligand binding, receptor activation, and biased signaling, thereby enabling the design of more selective agonists with improved safety profiles. Combination therapies targeting MC4R alongside glucagon-like peptide-1 mimetics and other agents regulating metabolic pathways have shown promise to enhance weight loss. MC4R modulators are also implicated in treating other disorders, including melanocortin signaling dysfunction. These progresses call for renewed efforts in developing the next-generation MC4R-based therapies against metabolic diseases.
History
DepositionDec 17, 2025-
Header (metadata) releaseAug 12, 2026-
Map releaseAug 12, 2026-
UpdateAug 26, 2026-
Current statusAug 26, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_67804.png

Downloads & links

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Map

FileDownload / File: emd_67804.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.03 Å/pix.
x 256 pix.
= 263.68 Å		1.03 Å/pix.
x 256 pix.
= 263.68 Å		1.03 Å/pix.
x 256 pix.
= 263.68 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.03 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.1
Minimum - Maximum-0.5482798 - 1.776636
Average (Standard dev.)0.0052023963 (±0.029158855)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 263.68 Å
α=β=γ: 90.0 °

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Supplemental data

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Sample components

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Entire : Cryo-EM structure of setmelanotide-bound human melanocortin recep...

EntireName: Cryo-EM structure of setmelanotide-bound human melanocortin receptor 4 in complex with Gq protein
Components
  • Complex: Cryo-EM structure of setmelanotide-bound human melanocortin receptor 4 in complex with Gq protein
    • Protein or peptide: Setmelanotide
    • Protein or peptide: Melanocortin receptor 4,LgBiT subunit
    • Protein or peptide: G subunit q (Gi1-Gq chimeric)
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,HiBiT
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
  • Ligand: CALCIUM ION

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Supramolecule #1: Cryo-EM structure of setmelanotide-bound human melanocortin recep...

SupramoleculeName: Cryo-EM structure of setmelanotide-bound human melanocortin receptor 4 in complex with Gq protein
type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Setmelanotide

MacromoleculeName: Setmelanotide / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 1.081297 KDa
SequenceString:
RC(DAL)H(DPN)RWC

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Macromolecule #2: Melanocortin receptor 4,LgBiT subunit

MacromoleculeName: Melanocortin receptor 4,LgBiT subunit / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 55.571496 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MVNSTHRGMH TSLHLWNRSS YRLHSNASES LGKGYSDGGC YEQLFVSPEV FVTLGVISLL ENILVIVAIA KNKNLHSPMY FFICSLAVA DMLVSVSNGS ETIVITLLNS TDTDAQSFTV NIDNVIDSVI CSSLLASICS LLSIAVDRYF TIFYALQYHN I MTVKRVGI ...String:
MVNSTHRGMH TSLHLWNRSS YRLHSNASES LGKGYSDGGC YEQLFVSPEV FVTLGVISLL ENILVIVAIA KNKNLHSPMY FFICSLAVA DMLVSVSNGS ETIVITLLNS TDTDAQSFTV NIDNVIDSVI CSSLLASICS LLSIAVDRYF TIFYALQYHN I MTVKRVGI IISCIWAACT VSGILFIIYS DSSAVIICLI TMFFTMLALM ASLYVHMFLM ARLHIKRIAV LPGTGAIRQG AN MKGAITL TILIGVFVVC WAPFFLHLIF YISCPQNPYC VCFMSHFNLY LILIMCNSII DPLIYALRSQ ELRKTFKEII CCY PLGGLC DLSSRYGSSG GGGSGGGGSS GVFTLEDFVG DWEQTAAYNL DQVLEQGGVS SLLQNLAVSV TPIQRIVRSG ENAL KIDIH VIIPYEGLSA DQMAQIEEVF KVVYPVDDHH FKVILPYGTL VIDGVTPNML NYFGRPYEGI AVFDGKKITV TGTLW NGNK IIDERLITPD GSMLFRVTIN S

UniProtKB: Melanocortin receptor 4

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Macromolecule #3: G subunit q (Gi1-Gq chimeric)

MacromoleculeName: G subunit q (Gi1-Gq chimeric) / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.724383 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
MGCTLSAEDK AAVERSKMIE KQLQKDKQVY RRTLRLLLLG ADNSGKSTIV KQMRIYHVNG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTSGIFETK FQVDKVNFHM FDVGAQRDER RKWIQCFNDV TAIIFVVDSS DYNRLQEALN DF KSIWNNR WLRTISVILF LNKQDLLAEK VLAGKSKIED YFPEFARYTT PEDATPEPGE DPRVTRAKYF IRKEFVDIST ASG DGRHIC YPHFTCSVDT ENARRIFNDC KDIILQMNLR EYNLV

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Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,HiBiT

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,HiBiT
type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: synthetic construct (others)
Molecular weightTheoretical: 40.226992 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
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 #5: 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: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Bos taurus (domestic cattle)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
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 #6: CALCIUM ION

MacromoleculeName: CALCIUM ION / type: ligand / ID: 6 / Number of copies: 1 / Formula: CA
Molecular weightTheoretical: 40.078 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: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeTFS 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: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.2 µm / Nominal defocus min: 1.2 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: NONE
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.11 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.05) / Number images used: 58767
Initial angle assignmentType: COMMON LINE
Final angle assignmentType: MAXIMUM LIKELIHOOD

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