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- PDB-9k3p: Cryo-EM structure of the unliganded human melanocortin receptor 1... -

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Basic information

Entry
Database: PDB / ID: 9k3p
TitleCryo-EM structure of the unliganded human melanocortin receptor 1 (MC1R)-Gs complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,LgBiT subunit
  • Nb35
  • scFv16
KeywordsMEMBRANE PROTEIN / human melanocortin receptor 1 / G protein-coupled receptor / unliganded constitutive activity
Function / homology
Function and homology information


melanocyte-stimulating hormone receptor activity / positive regulation of feeding behavior / melanocortin receptor activity / melanin biosynthetic process / UV protection / UV-damage excision repair / G protein-coupled peptide receptor activity / Activation of G protein gated Potassium channels / G-protein activation / G beta:gamma signalling through PI3Kgamma ...melanocyte-stimulating hormone receptor activity / positive regulation of feeding behavior / melanocortin receptor activity / melanin biosynthetic process / UV protection / UV-damage excision repair / G protein-coupled peptide receptor activity / 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 / regulation of metabolic process / 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 / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (z) signalling events / Extra-nuclear estrogen signaling / G alpha (s) signalling events / G alpha (q) signalling events / pigmentation / G alpha (i) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Vasopressin regulates renal water homeostasis via Aquaporins / hormone binding / positive regulation of cAMP/PKA signal transduction / negative regulation of tumor necrosis factor production / PKA activation in glucagon signalling / developmental growth / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / hair follicle placode formation / D1 dopamine receptor binding / intracellular transport / adenylate cyclase inhibitor activity / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / activation of adenylate cyclase activity / Hedgehog 'off' state / positive regulation of protein localization to cell cortex / T cell migration / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / adenylate cyclase-activating adrenergic receptor signaling pathway / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / sensory perception of pain / Transcriptional and post-translational regulation of MITF-M expression and activity / cellular response to forskolin / cellular response to glucagon stimulus / regulation of insulin secretion / regulation of mitotic spindle organization / Peptide ligand-binding receptors / adenylate cyclase activator activity / trans-Golgi network membrane / Regulation of insulin secretion / negative regulation of inflammatory response to antigenic stimulus / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / negative regulation of insulin secretion / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / bone development / response to peptide hormone / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / centriolar satellite / G-protein beta/gamma-subunit complex binding / platelet aggregation / Olfactory Signaling Pathway / Activation of the phototransduction cascade / cognition / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / adenylate cyclase-activating G protein-coupled receptor signaling pathway / 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
Similarity search - Function
Melanocyte-stimulating hormone receptor / Melanocortin/ACTH receptor / G-protein alpha subunit, group S / G-protein alpha subunit, group I / 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 ...Melanocyte-stimulating hormone receptor / Melanocortin/ACTH receptor / G-protein alpha subunit, group S / G-protein alpha subunit, group I / 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
Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Guanine nucleotide-binding protein G(i) subunit alpha-1 / Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 / Melanocyte-stimulating hormone receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.98 Å
AuthorsFeng, W.B. / Zhou, Q.T. / Zheng, C. / Yang, D.H. / Wang, M.W.
Funding support China, 5items
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
Other governmentZDKJ2021028
CitationJournal: Structure / Year: 2025
Title: Structural basis for the constitutive activity of the melanocortin receptor family.
Authors: Wenbo Feng / Qingtong Zhou / Chang Zheng / Dehua Yang / Ming-Wei Wang /
Abstract: The constitutive activity of melanocortin receptors (MCRs) is integral to several physiological processes. The unliganded cryo-electron microscopy structures of MC1R, MC2R, MC3R, MC4R, and MC5R in ...The constitutive activity of melanocortin receptors (MCRs) is integral to several physiological processes. The unliganded cryo-electron microscopy structures of MC1R, MC2R, MC3R, MC4R, and MC5R in complex with G proteins determined at global resolutions of 2.98 Å, 3.01 Å, 2.75 Å, 3.12 Å, and 2.86 Å, respectively, revealed that their binding poses and interactions with G are similar to those of agonist-bound MCRs. The extracellular regions of the transmembrane helices (TMs) exhibit distinct conformational rearrangements, characterized by varying shifts of TM3 and outward displacements of TM4. These variations represent unique structural features of constitutively activated MCRs. Unassigned electron densities were observed within the orthosteric pockets where extensive interactions with cognate ligands occur. In addition, zinc ions, but not calcium, positively regulated MC4R activity in a dose-dependent manner. Our findings provide valuable insights into the molecular mechanisms underlying MCR basal activity and highlight the role of divalent ions in receptor activation.
History
DepositionOct 19, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Aug 6, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,LgBiT subunit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,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
N: Nb35
S: scFv16


Theoretical massNumber of molelcules
Total (without water)191,0196
Polymers191,0196
Non-polymers00
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 RN

#1: Protein Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,Melanocyte-stimulating hormone receptor,LgBiT subunit / MSH-R / Melanocortin receptor 1 / MC1-R


Mass: 53336.191 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: MC1R, MSHR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q01726
#5: Protein Nb35


Mass: 17352.498 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Escherichia coli BL21(DE3) (bacteria)

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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#2: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1,Guanine nucleotide-binding protein G(s) subunit alpha isoforms short / Adenylate cyclase-inhibiting G alpha protein / Adenylate cyclase-stimulating G alpha protein


Mass: 41879.465 Da / Num. of mol.: 1
Mutation: G49D,E50N,L63Y,G226A,A249D,S252D,L272D,A366S,I372A,V375I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1, GNAS, GNAS1, GSP / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P63096, UniProt: P63092, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#3: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1,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.) Homo sapiens (human), (gene. exp.) synthetic construct (others)
Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#4: 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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Antibody , 1 types, 1 molecules S

#6: Antibody scFv16


Mass: 30363.043 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) synthetic construct (others) / Production host: Spodoptera frugiperda (fall armyworm)

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Details

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 unliganded human melanocortin receptor 1 in complex with G protein
Type: COMPLEX / Entity ID: all / Source: RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
21Bos taurus (domestic cattle)9913
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Spodoptera frugiperda (fall armyworm)7108
21Escherichia coli BL21(DE3) (bacteria)469008
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: OTHER / Accelerating voltage: 300 kV / Illumination mode: OTHER
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
1cryoSPARCparticle selection
2PHENIX1.18.2_3874:model refinement
13Coot3D reconstruction
14PHENIX3D reconstruction
CTF correctionType: NONE
3D reconstructionResolution: 2.98 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 875641 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0059607
ELECTRON MICROSCOPYf_angle_d0.68813033
ELECTRON MICROSCOPYf_dihedral_angle_d7.5971332
ELECTRON MICROSCOPYf_chiral_restr0.0471485
ELECTRON MICROSCOPYf_plane_restr0.0041665

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