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- PDB-9k3l: Cryo-EM structure of the unliganded human melanocortin receptor 2... -

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Basic information

Entry
Database: PDB / ID: 9k3l
TitleCryo-EM structure of the unliganded human melanocortin receptor 2 (MC2R)-Gs complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor,LgBiT subunit
  • Nb35
  • scFv16
KeywordsMEMBRANE PROTEIN / human melanocortin receptor 2 / G protein-coupled receptor / unliganded / constitutive activity
Function / homology
Function and homology information


corticotropin receptor activity / Defective ACTH causes obesity and POMCD / melanocortin 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 ...corticotropin receptor activity / Defective ACTH causes obesity and POMCD / melanocortin 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 / 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 / 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 / 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 / G protein-coupled receptor activity / 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 / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / sensory perception of smell
Similarity search - Function
Adrenocorticotrophin (ACTH) 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 ...Adrenocorticotrophin (ACTH) 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 / Adrenocorticotropic hormone receptor
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
Bos taurus (domestic cattle)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.01 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
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,HiBiT
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
N: Nb35
R: Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor,LgBiT subunit
S: scFv16


Theoretical massNumber of molelcules
Total (without water)190,2416
Polymers190,2416
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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Guanine nucleotide-binding protein ... , 3 types, 3 molecules ABG

#1: 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 / Cell line (production host): High 5 / 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
#2: 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,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
#3: 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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Protein , 2 types, 2 molecules NR

#4: 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)
#5: Protein Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor,LgBiT subunit / ACTH receptor / ACTH-R / Adrenocorticotropin receptor / Melanocortin receptor 2 / MC2-R


Mass: 52557.422 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: MC2R, ACTHR / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q01718

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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 2 in complex with Gs 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)Organism: Spodoptera frugiperda (fall armyworm)
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: SPOT SCAN
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 softwareName: PHENIX / Version: 1.18.2_3874: / Category: model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.01 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 172062 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0059443
ELECTRON MICROSCOPYf_angle_d0.66112820
ELECTRON MICROSCOPYf_dihedral_angle_d5.3811307
ELECTRON MICROSCOPYf_chiral_restr0.0461474
ELECTRON MICROSCOPYf_plane_restr0.0041629

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