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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 receptor activity / corticotropin hormone receptor binding / type 5 melanocortin receptor binding / Defective ACTH causes obesity and POMCD / type 1 melanocortin receptor binding / type 3 melanocortin receptor binding / type 4 melanocortin receptor binding / melanocortin receptor activity / signaling receptor regulator activity / sensory perception of chemical stimulus ...corticotropin receptor activity / corticotropin hormone receptor binding / type 5 melanocortin receptor binding / Defective ACTH causes obesity and POMCD / type 1 melanocortin receptor binding / type 3 melanocortin receptor binding / type 4 melanocortin receptor binding / melanocortin receptor activity / signaling receptor regulator activity / sensory perception of chemical stimulus / mu-type opioid receptor binding / corticotropin-releasing hormone receptor 1 binding / negative regulation of adenylate cyclase activity / negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / regulation of metabolic process / GTP metabolic process / negative regulation of protein localization to plasma membrane / beta-2 adrenergic receptor binding / G protein-coupled dopamine receptor signaling pathway / positive regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway / PKA activation in glucagon signalling / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of macroautophagy / developmental growth / D1 dopamine receptor binding / Adenylate cyclase inhibitory pathway / Hedgehog 'off' state / insulin-like growth factor receptor binding / adenylate cyclase activator activity / ionotropic glutamate receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Peptide ligand-binding receptors / protein localization to plasma membrane / G protein-coupled receptor binding / G protein-coupled receptor activity / electron transport chain / G-protein beta/gamma-subunit complex binding / bone development / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / hormone activity / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / platelet aggregation / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / positive regulation of cold-induced thermogenesis / phospholipase C-activating G protein-coupled receptor signaling pathway / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / Ras protein signal transduction / Extra-nuclear estrogen signaling / cell population proliferation / periplasmic space / electron transfer activity / apical plasma membrane / iron ion binding / G protein-coupled receptor signaling pathway
Similarity search - Function
Adrenocorticotrophin (ACTH) receptor / Melanocortin-2 receptor accessory protein family / Melanocortin-2 receptor accessory protein family / Pro-opiomelanocortin / Pro-opiomelanocortin/corticotropin, ACTH, central region / Corticotropin ACTH domain / Corticotropin ACTH domain / Melanocortin/ACTH receptor / Cytochrome b562 / Cytochrome b562 ...Adrenocorticotrophin (ACTH) receptor / Melanocortin-2 receptor accessory protein family / Melanocortin-2 receptor accessory protein family / Pro-opiomelanocortin / Pro-opiomelanocortin/corticotropin, ACTH, central region / Corticotropin ACTH domain / Corticotropin ACTH domain / Melanocortin/ACTH receptor / Cytochrome b562 / Cytochrome b562 / G-protein alpha subunit, group S / Cytochrome c/b562 / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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. / WD domain, G-beta repeat / 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) 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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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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

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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
21Homo sapiens (human)9606
32Homo sapiens (human)9606
43Homo sapiens (human)9606
54Homo sapiens (human)9606
65Homo sapiens (human)9606
76Homo sapiens (human)9606
87Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
21Trichoplusia 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
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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