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- PDB-21lt: Cryo-EM structure of the setmelanotide-bound human melanocortin r... -

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Basic information

Entry
Database: PDB / ID: 21lt
TitleCryo-EM structure of the setmelanotide-bound human melanocortin receptor 4 (MC4R)-Gq complex
Components
  • (Guanine nucleotide-binding protein ...) x 2
  • G subunit q (Gi1-Gq chimeric)
  • Melanocortin receptor 4,LgBiT subunit
  • Setmelanotide
KeywordsMEMBRANE PROTEIN / human melanocortin receptor 4 / G protein-coupled receptor / setmelanotide / Gq
Function / homology
Function and homology information


response to melanocyte-stimulating hormone / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / corticotropin receptor activity / non-motile cilium membrane / regulation of feeding behavior / 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 / non-motile cilium membrane / regulation of feeding behavior / 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 / photoreceptor outer segment membrane / negative regulation of feeding behavior / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / 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 / photoreceptor inner segment / Transcriptional and post-translational regulation of MITF-M expression and activity / 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 / cellular response to prostaglandin E stimulus / positive regulation of cytosolic calcium ion concentration / heterotrimeric G-protein complex / G-protein beta-subunit binding / adenylate cyclase-activating G protein-coupled receptor signaling pathway / signaling receptor complex adaptor activity / cell body / GTPase binding / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / 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)
Rattus norvegicus (Norway rat)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.11 Å
AuthorsFeng, W.B. / Zhou, Q.T. / Wang, M.W.
Funding support China, 6items
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: Feng, W. / Zhou, Q. / Wang, M.W.
History
DepositionDec 17, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 12, 2026Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Aug 12, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
P: Setmelanotide
R: Melanocortin receptor 4,LgBiT subunit
A: G subunit q (Gi1-Gq chimeric)
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,HiBiT
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)146,5056
Polymers146,4655
Non-polymers401
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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Protein , 2 types, 2 molecules RA

#2: Protein Melanocortin receptor 4,LgBiT subunit / MC4-R


Mass: 55571.496 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: MC4R / Production host: Trichoplusia ni (cabbage looper) / Strain (production host): High 5 / References: UniProt: P32245
#3: Protein G subunit q (Gi1-Gq chimeric)


Mass: 41724.383 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Production host: Trichoplusia ni (cabbage looper)

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Guanine nucleotide-binding protein ... , 2 types, 2 molecules BG

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


Mass: 40226.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Rattus norvegicus (Norway rat), (gene. exp.) synthetic construct (others)
Gene: Gnb1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P54311
#5: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / G gamma-I


Mass: 7861.143 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Bos taurus (domestic cattle) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P63212

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Protein/peptide / Non-polymers , 2 types, 2 molecules P

#1: Protein/peptide Setmelanotide


Mass: 1081.297 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)
#6: Chemical ChemComp-CA / CALCIUM ION


Mass: 40.078 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Ca / Feature type: SUBJECT OF INVESTIGATION

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Details

Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Cryo-EM structure of setmelanotide-bound human melanocortin receptor 4 in complex with Gq protein
Type: COMPLEX / Entity ID: #1-#5 / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
21Homo sapiens (human)9606
31Rattus norvegicus (Norway rat)10116
41Bos taurus (domestic cattle)9913
Source (recombinant)Organism: Trichoplusia ni (cabbage looper)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 2200 nm / Nominal defocus min: 1200 nm
Image recordingElectron dose: 80 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.05particle selection
2PHENIX1.18.2_3874model refinement
13cryoSPARC4.053D reconstruction
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.11 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 58767 / Symmetry type: POINT

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