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- EMDB-13454: Active Melanocortin-4 receptor (MC4R)- Gs protein complex bound t... -
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Open data
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Basic information
Entry | Database: EMDB / ID: EMD-13454 | ||||||||||||
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Title | Active Melanocortin-4 receptor (MC4R)- Gs protein complex bound to agonist NDP-alpha-MSH at 2.86 A resolution. | ||||||||||||
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Function / homology | ![]() regulation of eating behavior / melanocyte-stimulating hormone receptor activity / response to melanocyte-stimulating hormone / melanocortin receptor activity / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma ...regulation of eating behavior / melanocyte-stimulating hormone receptor activity / response to melanocyte-stimulating hormone / melanocortin receptor activity / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Prostacyclin signalling through prostacyclin receptor / G alpha (z) signalling events / Glucagon-type ligand receptors / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / G beta:gamma signalling through BTK / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Thromboxane signalling through TP receptor / Thrombin signalling through proteinase activated receptors (PARs) / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Ca2+ pathway / G alpha (s) signalling events / G alpha (q) signalling events / Extra-nuclear estrogen signaling / G alpha (12/13) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / regulation of grooming behavior / G alpha (i) signalling events / GPER1 signaling / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADP signalling through P2Y purinoceptor 1 / energy reserve metabolic process / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors / Thromboxane signalling through TP receptor / Sensory perception of sweet, bitter, and umami (glutamate) taste / G beta:gamma signalling through PI3Kgamma / G beta:gamma signalling through CDC42 / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / neuropeptide binding / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / regulation of metabolic process / feeding behavior / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / G alpha (i) signalling events / alkylglycerophosphoethanolamine phosphodiesterase activity / insulin secretion / photoreceptor outer segment membrane / positive regulation of bone resorption / spectrin binding / negative regulation of feeding behavior / diet induced thermogenesis / peptide hormone binding / PKA activation in glucagon signalling / hair follicle placode formation / photoreceptor outer segment / developmental growth / Transcriptional and post-translational regulation of MITF-M expression and activity / D1 dopamine receptor binding / intracellular transport / Hedgehog 'off' state / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / cardiac muscle cell apoptotic process / adenylate cyclase activator activity / photoreceptor inner segment / Peptide ligand-binding receptors / trans-Golgi network membrane / response to insulin / G-protein beta/gamma-subunit complex binding / bone development / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / cognition / platelet aggregation / 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 / adenylate cyclase-activating dopamine receptor signaling pathway / cellular response to prostaglandin E stimulus / GPER1 signaling / G-protein beta-subunit binding / heterotrimeric G-protein complex / sensory perception of smell / signaling receptor complex adaptor activity Similarity search - Function | ||||||||||||
Biological species | ![]() ![]() ![]() ![]() ![]() ![]() ![]() | ||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.86 Å | ||||||||||||
![]() | Heyder NA / Schmidt A / Kleinau G / Hilal T / Scheerer P | ||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structures of active melanocortin-4 receptor-Gs-protein complexes with NDP-α-MSH and setmelanotide. Authors: Nicolas A Heyder / Gunnar Kleinau / David Speck / Andrea Schmidt / Sarah Paisdzior / Michal Szczepek / Brian Bauer / Anja Koch / Monique Gallandi / Dennis Kwiatkowski / Jörg Bürger / ...Authors: Nicolas A Heyder / Gunnar Kleinau / David Speck / Andrea Schmidt / Sarah Paisdzior / Michal Szczepek / Brian Bauer / Anja Koch / Monique Gallandi / Dennis Kwiatkowski / Jörg Bürger / Thorsten Mielke / Annette G Beck-Sickinger / Peter W Hildebrand / Christian M T Spahn / Daniel Hilger / Magdalena Schacherl / Heike Biebermann / Tarek Hilal / Peter Kühnen / Brian K Kobilka / Patrick Scheerer / ![]() ![]() Abstract: The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of ...The melanocortin-4 receptor (MC4R), a hypothalamic master regulator of energy homeostasis and appetite, is a class A G-protein-coupled receptor and a prime target for the pharmacological treatment of obesity. Here, we present cryo-electron microscopy structures of MC4R-Gs-protein complexes with two drugs recently approved by the FDA, the peptide agonists NDP-α-MSH and setmelanotide, with 2.9 Å and 2.6 Å resolution. Together with signaling data from structure-derived MC4R mutants, the complex structures reveal the agonist-induced origin of transmembrane helix (TM) 6-regulated receptor activation. The ligand-binding modes of NDP-α-MSH, a high-affinity linear variant of the endogenous agonist α-MSH, and setmelanotide, a cyclic anti-obesity drug with biased signaling toward Gq/11, underline the key role of TM3 in ligand-specific interactions and of calcium ion as a ligand-adaptable cofactor. The agonist-specific TM3 interplay subsequently impacts receptor-Gs-protein interfaces at intracellular loop 2, which also regulates the G-protein coupling profile of this promiscuous receptor. Finally, our structures reveal mechanistic details of MC4R activation/inhibition, and provide important insights into the regulation of the receptor signaling profile which will facilitate the development of tailored anti-obesity drugs. | ||||||||||||
History |
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Structure visualization
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Structure viewer | EM map: ![]() ![]() ![]() |
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 4.9 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 23 KB 23 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 9.7 KB | Display | ![]() |
Images | ![]() | 67 KB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 7pivMC ![]() 7piuC C: citing same article ( M: atomic model generated by this map |
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Similar structure data |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Voxel size | X=Y=Z: 0.832 Å | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Details | EMDB XML:
CCP4 map header:
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-Supplemental data
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Sample components
-Entire : Ternary complex of the NDP-alpha-MSH activated melanocortin 4 rec...
Entire | Name: Ternary complex of the NDP-alpha-MSH activated melanocortin 4 receptor (MC4R) Gs protein complex stabilized by nanobody 35 |
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Components |
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-Supramolecule #1: Ternary complex of the NDP-alpha-MSH activated melanocortin 4 rec...
Supramolecule | Name: Ternary complex of the NDP-alpha-MSH activated melanocortin 4 receptor (MC4R) Gs protein complex stabilized by nanobody 35 type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#6 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 144.6 kDa/nm |
-Macromolecule #1: Melanocortin receptor 4
Macromolecule | Name: Melanocortin receptor 4 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 38.69852 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: DYKDDDDKMV NSTHRGMHTS LHLWNRSSYR LHSNASESLG KGYSDGGCYE QLFVSPEVFV TLGVISLLEN ILVIVAIAKN KNLHSPMYF FICSLAVADM LVSVSNGSET IVITLLNSTD TDAQSFTVNI DNVIDSVICS SLLASICSLL SIAVDRYFTI F YALQYHNI ...String: DYKDDDDKMV NSTHRGMHTS LHLWNRSSYR LHSNASESLG KGYSDGGCYE QLFVSPEVFV TLGVISLLEN ILVIVAIAKN KNLHSPMYF FICSLAVADM LVSVSNGSET IVITLLNSTD TDAQSFTVNI DNVIDSVICS SLLASICSLL SIAVDRYFTI F YALQYHNI MTVKRVGIII SCIWAACTVS GILFIIYSDS SAVIICLITM FFTMLALMAS LYVHMFLMAR LHIKRIAVLP GT GAIRQGA NMKGAITLTI LIGVFVVCWA PFFLHLIFYI SCPQNPYCVC FMSHFNLYLI LIMCNSIIDP LIYALRSQEL RKT FKEIIC CYPLGGLCDL SSRYLEVLFQ |
-Macromolecule #2: NDP-alpha-MSH (other names Afamelanotide; Scenesse)
Macromolecule | Name: NDP-alpha-MSH (other names Afamelanotide; Scenesse) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: synthetic construct (others) |
Molecular weight | Theoretical: 1.632863 KDa |
Sequence | String: (ACE)SYS(NLE)EH(DPN)RW GKPV(NH2) |
-Macromolecule #3: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit...
Macromolecule | Name: Isoform Gnas-2 of Guanine nucleotide-binding protein G(s) subunit alpha isoforms short type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 44.32616 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG DSEKATKVQD IKNNLKEAI ETIVAAMSNL VPPVELANPE NQFRVDYILS VMNVPDFDFP PEFYEHAKAL WEDEGVRACY ERSNEYQLID C AQYFLDKI ...String: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKSTIVKQM RILHVNGFNG DSEKATKVQD IKNNLKEAI ETIVAAMSNL VPPVELANPE NQFRVDYILS VMNVPDFDFP PEFYEHAKAL WEDEGVRACY ERSNEYQLID C AQYFLDKI DVIKQADYVP SDQDLLRCRV LTSGIFETKF QVDKVNFHMF DVGGQRDERR KWIQCFNDVT AIIFVVASSS YN MVIREDN QTNRLQEALN LFKSIWNNRW LRTISVILFL NKQDLLAEKV LAGKSKIEDY FPEFARYTTP EDATPEPGED PRV TRAKYF IRDEFLRIST ASGDGRHYCY PHFTCAVDTE NIRRVFNDCR DIIQRMHLRQ YELL |
-Macromolecule #4: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 37.728152 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD ...String: GPGSSGSELD QLRQEAEQLK NQIRDARKAC ADATLSQITN NIDPVGRIQM RTRRTLRGHL AKIYAMHWGT DSRLLVSASQ DGKLIIWDS YTTNKVHAIP LRSSWVMTCA YAPSGNYVAC GGLDNICSIY NLKTREGNVR VSRELAGHTG YLSCCRFLDD N QIVTSSGD TTCALWDIET GQQTTTFTGH TGDVMSLSLA PDTRLFVSGA CDASAKLWDV REGMCRQTFT GHESDINAIC FF PNGNAFA TGSDDATCRL FDLRADQELM TYSHDNIICG ITSVSFSKSG RLLLAGYDDF NCNVWDALKA DRAGVLAGHD NRV SCLGVT DDGMAVATGS WDSFLKIWN |
-Macromolecule #5: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 7.861143 KDa |
Recombinant expression | Organism: ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L |
-Macromolecule #6: Camelid antibody VHH fragment - nanobody 35
Macromolecule | Name: Camelid antibody VHH fragment - nanobody 35 / type: protein_or_peptide / ID: 6 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() ![]() |
Molecular weight | Theoretical: 14.71432 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSSH HHHHH |
-Macromolecule #7: CALCIUM ION
Macromolecule | Name: CALCIUM ION / type: ligand / ID: 7 / Number of copies: 1 / Formula: CA |
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Molecular weight | Theoretical: 40.078 Da |
-Macromolecule #8: water
Macromolecule | Name: water / type: ligand / ID: 8 / Number of copies: 115 / Formula: HOH |
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Molecular weight | Theoretical: 18.015 Da |
Chemical component information | ![]() ChemComp-HOH: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 1.2 mg/mL | ||||||||||||||||||||||||
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Buffer | pH: 7.5 Component:
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Grid | Model: UltrAuFoil R1.2/1.3 / Material: GOLD / Pretreatment - Type: GLOW DISCHARGE | ||||||||||||||||||||||||
Vitrification | Cryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 283 K / Instrument: FEI VITROBOT MARK IV |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: FEI FALCON III (4k x 4k) / Detector mode: COUNTING / Number grids imaged: 1 / Number real images: 5618 / Average exposure time: 40.78 sec. / Average electron dose: 40.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | C2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 0.8 µm / Nominal magnification: 96000 |
Sample stage | Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |