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- PDB-8inr: Cryo-EM structure of the alpha-MSH-bound human melanocortin recep... -

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Basic information

Entry
Database: PDB / ID: 8inr
TitleCryo-EM structure of the alpha-MSH-bound human melanocortin receptor 5 (MC5R)-Gs complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • HA signal peptide,Melanocortin receptor 5,LgBiT subunit
  • alpha-melanocyte-stimulating hormone
KeywordsMEMBRANE PROTEIN / human melanocortin receptor 5 / G protein-coupled receptor / ligand recpgnition
Function / homology
Function and homology information


corticotropin receptor activity / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / negative regulation of immune response / 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 ...corticotropin receptor activity / melanocyte-stimulating hormone receptor activity / melanocortin receptor activity / negative regulation of immune response / 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 (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 / temperature homeostasis / adenylate cyclase-activating G protein-coupled bile acid receptor signaling pathway / adenylate cyclase-activating serotonin receptor signaling pathway / hormone binding / positive regulation of exocytosis / regulation of skeletal muscle contraction / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / intracellular transport / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / D1 dopamine receptor binding / vascular endothelial cell response to laminar fluid shear stress / renal water homeostasis / Hedgehog 'off' state / activation of adenylate cyclase activity / cellular response to acidic pH / adenylate cyclase-activating adrenergic receptor signaling pathway / adenylate cyclase inhibitor activity / positive regulation of protein localization to cell cortex / T cell migration / positive regulation of relaxation of smooth muscle / Adenylate cyclase inhibitory pathway / D2 dopamine receptor binding / Transcriptional and post-translational regulation of MITF-M expression and activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / cellular response to glucagon stimulus / intracellular glucose homeostasis / cellular response to forskolin / viral budding from plasma membrane / Peptide ligand-binding receptors / positive regulation of insulin secretion involved in cellular response to glucose stimulus / regulation of mitotic spindle organization / adenylate cyclase activator activity / chemokine-mediated signaling pathway / trans-Golgi network membrane / negative regulation of inflammatory response to antigenic stimulus / neuropeptide signaling pathway / Regulation of insulin secretion / response to prostaglandin E / positive regulation of cholesterol biosynthetic process / negative regulation of insulin secretion / bone development / G protein-coupled receptor binding / response to peptide hormone / platelet aggregation / cognition / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / centriolar satellite / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / positive regulation of insulin secretion / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / 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 / Glucagon-type ligand receptors
Similarity search - Function
Melanocortin 5 receptor / Melanocortin receptor 3-5 / Melanocortin/ACTH receptor / G-protein alpha subunit, group S / Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein / G-protein alpha subunit, group I ...Melanocortin 5 receptor / Melanocortin receptor 3-5 / Melanocortin/ACTH receptor / G-protein alpha subunit, group S / Haemagglutinin, influenzavirus A / Haemagglutinin, HA1 chain, alpha/beta domain superfamily / Haemagglutinin / Haemagglutinin, influenzavirus A/B / Viral capsid/haemagglutinin protein / 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. / 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 / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
Hemagglutinin / Melanocortin receptor 5 / 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
Similarity search - Component
Biological speciesInfluenza A virus
Homo sapiens (human)
Bos taurus (domestic cattle)
synthetic construct (others)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.73 Å
AuthorsFeng, W.B. / Zhou, Q.T. / Chen, X.Y. / Dai, A.T. / Cai, X.Q. / Liu, X. / Zhao, F.H. / Chen, Y. / Ye, C.Y. / Xu, Y.N. ...Feng, W.B. / Zhou, Q.T. / Chen, X.Y. / Dai, A.T. / Cai, X.Q. / Liu, X. / Zhao, F.H. / Chen, Y. / Ye, C.Y. / Xu, Y.N. / Cong, Z.T. / Li, H. / Lin, S. / Yang, D.H. / Wang, M.W.
Funding support China, 11items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)81872915 China
National Natural Science Foundation of China (NSFC)82073904 China
National Natural Science Foundation of China (NSFC)82121005 China
National Natural Science Foundation of China (NSFC)81973373 China
National Natural Science Foundation of China (NSFC)21704064 China
Other government2018YFA0507000
Other government2018ZX09735-001
Other government2018ZX09711002-002-005
Other governmentSTI2030-Major project 2021ZD0203400
Other governmentZDKJ2021028
Other government21JC1401600
CitationJournal: Cell Discov / Year: 2023
Title: Structural insights into ligand recognition and subtype selectivity of the human melanocortin-3 and melanocortin-5 receptors.
Authors: Wenbo Feng / Qingtong Zhou / Xianyue Chen / Antao Dai / Xiaoqing Cai / Xiao Liu / Fenghui Zhao / Yan Chen / Chenyu Ye / Yingna Xu / Zhaotong Cong / Hao Li / Shi Lin / Dehua Yang / Ming-Wei Wang /
Abstract: Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin ...Members of the melanocortin receptor (MCR) family that recognize different melanocortin peptides mediate a broad spectrum of cellular processes including energy homeostasis, inflammation and skin pigmentation through five MCR subtypes (MC1R-MC5R). The structural basis of subtype selectivity of the endogenous agonist γ-MSH and non-selectivity of agonist α-MSH remains elusive, as the two agonists are highly similar with a conserved HFRW motif. Here, we report three cryo-electron microscopy structures of MC3R-G in complex with γ-MSH and MC5R-G in the presence of α-MSH or a potent synthetic agonist PG-901. The structures reveal that α-MSH and γ-MSH adopt a "U-shape" conformation, penetrate into the wide-open orthosteric pocket and form massive common contacts with MCRs via the HFRW motif. The C-terminus of γ-MSH occupies an MC3R-specific complementary binding groove likely conferring subtype selectivity, whereas that of α-MSH distances itself from the receptor with neglectable contacts. PG-901 achieves the same potency as α-MSH with a shorter length by rebalancing the recognition site and mimicking the intra-peptide salt bridge in α-MSH by cyclization. Solid density confirmed the calcium ion binding in MC3R and MC5R, and the distinct modulation effects of divalent ions were demonstrated. Our results provide insights into ligand recognition and subtype selectivity among MCRs, and expand the knowledge of signal transduction among MCR family members.
History
DepositionMar 10, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Sep 20, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 23, 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
R: HA signal peptide,Melanocortin receptor 5,LgBiT subunit
L: alpha-melanocyte-stimulating hormone
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,HiBiT
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)148,5556
Polymers148,5155
Non-polymers401
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#3: 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,ten deletions and A249D,S252D,L272D,I372A,V375I,G226A,A366S
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
#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.) Homo sapiens (human) / Gene: GNB1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P62873
#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: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63212

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Protein / Protein/peptide / Non-polymers , 3 types, 3 molecules RL

#1: Protein HA signal peptide,Melanocortin receptor 5,LgBiT subunit


Mass: 56920.516 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Influenza A virus (A/Victoria/3/1975(H3N2)), (gene. exp.) Homo sapiens (human)
Gene: HA, MC5R / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P03435, UniProt: P33032
#2: Protein/peptide alpha-melanocyte-stimulating hormone


Mass: 1626.856 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: isolated from a genetically manipulated source
Formula: Ca

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Details

Has ligand of interestN
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 alpha-MSH-bound human melanocortin receptor 5 in complex with G protein
Type: COMPLEX / Entity ID: #1-#5 / Source: MULTIPLE SOURCES
Source (natural)Organism: Homo sapiens (human)
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: FEI TITAN 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

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.73 Å / Resolution method: DIFFRACTION PATTERN/LAYERLINES / Num. of particles: 568095 / Symmetry type: POINT
RefinementCross valid method: NONE
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
Displacement parametersBiso mean: 58.72 Å2
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0127364
ELECTRON MICROSCOPYf_angle_d0.8259962
ELECTRON MICROSCOPYf_dihedral_angle_d6.113995
ELECTRON MICROSCOPYf_chiral_restr0.0581132
ELECTRON MICROSCOPYf_plane_restr0.0051261

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