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- PDB-8gy7: Cryo-EM structure of ACTH-bound melanocortin-2 receptor in comple... -

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Entry
Database: PDB / ID: 8gy7
TitleCryo-EM structure of ACTH-bound melanocortin-2 receptor in complex with MRAP1 and Gs protein
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Corticotropin
  • Melanocortin-2 receptor accessory protein
  • Soluble cytochrome b562,Adrenocorticotropic hormone receptor,melanocortin-2 receptor,Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor
KeywordsMEMBRANE PROTEIN / melanocortin-2 receptor / MRAP1 / GPCR / ACTH
Function / homology
Function and homology information


corticotropin hormone receptor binding / type 5 melanocortin receptor binding / corticotropin receptor activity / type 1 melanocortin receptor binding / Defective ACTH causes obesity and POMCD / type 3 melanocortin receptor binding / type 4 melanocortin receptor binding / regulation of corticosterone secretion / adenylate cyclase-activating serotonin receptor signaling pathway / melanocortin receptor activity ...corticotropin hormone receptor binding / type 5 melanocortin receptor binding / corticotropin receptor activity / type 1 melanocortin receptor binding / Defective ACTH causes obesity and POMCD / type 3 melanocortin receptor binding / type 4 melanocortin receptor binding / regulation of corticosterone secretion / adenylate cyclase-activating serotonin receptor signaling pathway / melanocortin receptor activity / signaling receptor regulator activity / sensory perception of chemical stimulus / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / mu-type opioid receptor binding / negative regulation of adenylate cyclase activity / corticotropin-releasing hormone receptor 1 binding / GTP metabolic process / beta-2 adrenergic receptor binding / regulation of metabolic process / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / positive regulation of macroautophagy / PKA activation in glucagon signalling / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / developmental growth / D1 dopamine receptor binding / negative regulation of protein localization to plasma membrane / Hedgehog 'off' state / Adenylate cyclase inhibitory pathway / response to prostaglandin E / insulin-like growth factor receptor binding / adenylate cyclase regulator activity / ionotropic glutamate receptor binding / Peptide ligand-binding receptors / secretory granule / adenylate cyclase activator activity / protein localization to plasma membrane / electron transport chain / G protein-coupled receptor binding / G protein-coupled receptor activity / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / hormone activity / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / platelet aggregation / centriolar satellite / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / 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 / photoreceptor disc membrane / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / GDP binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / positive regulation of cold-induced thermogenesis / retina development in camera-type eye / G protein activity / GTPase binding / Ca2+ pathway / fibroblast proliferation / midbody / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Similarity search - Function
Melanocortin-2 receptor accessory protein family / Melanocortin-2 receptor accessory protein family / Adrenocorticotrophin (ACTH) receptor / Pro-opiomelanocortin / Pro-opiomelanocortin/corticotropin, ACTH, central region / : / Corticotropin ACTH domain / Corticotropin ACTH domain / Melanocortin/ACTH receptor / G-protein alpha subunit, group S ...Melanocortin-2 receptor accessory protein family / Melanocortin-2 receptor accessory protein family / Adrenocorticotrophin (ACTH) receptor / Pro-opiomelanocortin / Pro-opiomelanocortin/corticotropin, ACTH, central region / : / Corticotropin ACTH domain / Corticotropin ACTH domain / Melanocortin/ACTH receptor / G-protein alpha subunit, group S / Cytochrome b562 / Cytochrome b562 / Cytochrome c/b562 / G-protein alpha subunit, group I / YVTN repeat-like/Quinoprotein amine dehydrogenase / Serpentine type 7TM GPCR chemoreceptor Srsx / 7 Propeller / Methylamine Dehydrogenase; Chain H / 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 / Mainly Beta
Similarity search - Domain/homology
Guanine nucleotide-binding protein G(i) subunit alpha-3 / Soluble cytochrome b562 / 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 / Pro-opiomelanocortin / Adrenocorticotropic hormone receptor / Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / Melanocortin-2 receptor accessory protein
Similarity search - Component
Biological speciesHomo sapiens (human)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.3 Å
AuthorsLuo, P. / Feng, W.B. / Ma, S.S. / Dai, A.T. / Yuan, Q.N. / Wu, K. / Yang, D.H. / Wang, M.W. / Xu, H.E. / Jiang, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32171187 China
CitationJournal: Cell Res / Year: 2023
Title: Structural basis of signaling regulation of the human melanocortin-2 receptor by MRAP1.
Authors: Ping Luo / Wenbo Feng / Shanshan Ma / Antao Dai / Kai Wu / Xianyue Chen / Qingning Yuan / Xiaoqing Cai / Dehua Yang / Ming-Wei Wang / H Eric Xu / Yi Jiang /
Abstract: G protein-coupled receptors (GPCRs) are regulated by various downstream proteins, of which the melanocortin receptor accessory protein 1 (MRAP1) is closely involved in the regulation of melanocortin ...G protein-coupled receptors (GPCRs) are regulated by various downstream proteins, of which the melanocortin receptor accessory protein 1 (MRAP1) is closely involved in the regulation of melanocortin receptor 2 (MC2R). Assisted by MRAP1, MC2R responds to adrenocorticotropic hormone (ACTH) and stimulates glucocorticoid biogenesis and cortisol secretion. MC2R activation plays an essential role in the hypothalamic-pituitary-adrenal (HPA) axis that regulates stress response, while its dysfunction causes glucocorticoid insufficiency- or cortisol excess-associated disorders. Here, we present a cryo-electron microscopy (cryo-EM) structure of the ACTH-bound MC2R-G-MRAP1 complex. Our structure, together with mutagenesis analysis, reveals a unique sharp kink at the extracellular region of MRAP1 and the 'seat-belt' effect of MRAP1 on stabilizing ACTH binding and MC2R activation. Mechanisms of ACTH recognition by MC2R and receptor activation are also demonstrated. These findings deepen our understanding of GPCR regulation by accessory proteins and provide valuable insights into the ab initio design of therapeutic agents targeting MC2R.
History
DepositionSep 21, 2022Deposition site: PDBJ / Processing site: PDBE
Revision 1.0Jan 11, 2023Provider: repository / Type: Initial release
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Revision 1.1Sep 25, 2024Group: Data collection / Source and taxonomy
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / em_admin / em_entity_assembly_naturalsource / em_entity_assembly_recombinant
Item: _em_admin.last_update / _em_entity_assembly_naturalsource.id / _em_entity_assembly_recombinant.id
Revision 1.2Nov 13, 2024Group: Data collection / Structure summary
Category: em_admin / pdbx_entry_details / pdbx_modification_feature
Item: _em_admin.last_update / _pdbx_entry_details.has_protein_modification
Revision 1.3Jul 2, 2025Group: Data collection / Category: em_admin / em_software / Item: _em_admin.last_update / _em_software.name
Revision 1.1Jul 2, 2025Data content type: EM metadata / Data content type: EM metadata / EM metadata / Group: Data processing / Experimental summary / Data content type: EM metadata / EM metadata / Category: em_admin / em_software / Data content type: EM metadata / EM metadata / Item: _em_admin.last_update / _em_software.name

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-3,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
M: Corticotropin
P: Melanocortin-2 receptor accessory protein
R: Soluble cytochrome b562,Adrenocorticotropic hormone receptor,melanocortin-2 receptor,Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor
hetero molecules


Theoretical massNumber of molelcules
Total (without water)180,1427
Polymers180,1026
Non-polymers401
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
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-3,Guanine nucleotide-binding protein G(s) subunit alpha isoforms XLas / G(i) alpha-3 / Adenylate cyclase-stimulating G alpha protein / Extra large alphas protein / XLalphas


Mass: 41879.465 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI3, GNAS, GNAS1 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P08754, UniProt: Q5JWF2
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / 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: GNB1 / Production host: Trichoplusia ni (cabbage looper) / 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.) Homo sapiens (human) / Gene: GNG2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P59768

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Protein , 2 types, 2 molecules PR

#5: Protein Melanocortin-2 receptor accessory protein / B27 / Fat cell-specific low molecular weight protein / Fat tissue-specific low MW protein


Mass: 20486.178 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MRAP, C21orf61, FALP / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q8TCY5
#6: Protein Soluble cytochrome b562,Adrenocorticotropic hormone receptor,melanocortin-2 receptor,Adrenocorticotropic hormone receptor,Adrenocorticotropic hormone receptor / Cytochrome b-562 / ACTH receptor / ACTH-R / Adrenocorticotropin receptor / Melanocortin receptor 2 / MC2-R


Mass: 67391.219 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: cybC, MC2R, ACTHR / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P0ABE7, UniProt: Q01718

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

#4: Protein/peptide Corticotropin / Adrenocorticotropic hormone / ACTH


Mass: 2256.655 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others) / References: UniProt: P68000
#7: 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

Component
IDNameTypeEntity IDParent-IDSource
1ACTH-bound melanocortin-2 receptor in complex with MRAP1 and Gs proteinCOMPLEX#1-#60RECOMBINANT
2Guanine nucleotide-binding protein G(i) subunit alpha-1COMPLEX#11RECOMBINANT
3Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1COMPLEX#21RECOMBINANT
4Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2COMPLEX#31RECOMBINANT
5ACTHCOMPLEX#41RECOMBINANT
6MRAP1COMPLEX#51RECOMBINANT
7melanocortin-2 receptorCOMPLEX#61RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
11Homo sapiens (human)9606
22Homo sapiens (human)9606
33Homo sapiens (human)9606
44Homo sapiens (human)9606
55Homo sapiens (human)9606
66Homo sapiens (human)9606
77Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
11Trichoplusia ni (cabbage looper)7111
22Trichoplusia ni (cabbage looper)7111
33Trichoplusia ni (cabbage looper)7111
44Trichoplusia ni (cabbage looper)7111
55synthetic construct (others)32630
66Trichoplusia ni (cabbage looper)7111
77Trichoplusia ni (cabbage looper)7111
Buffer solutionpH: 7.2
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: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 1000 nm
Image recordingElectron dose: 60 e/Å2 / Film or detector model: GATAN K3 (6k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.19.2_4158: / Classification: refinement
EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.3 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59170 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0037813
ELECTRON MICROSCOPYf_angle_d0.56710579
ELECTRON MICROSCOPYf_dihedral_angle_d4.6121049
ELECTRON MICROSCOPYf_chiral_restr0.0421208
ELECTRON MICROSCOPYf_plane_restr0.0041335

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