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- EMDB-31982: MT2-remalteon-Gi complex -

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Basic information

Entry
Database: EMDB / ID: EMD-31982
TitleMT2-remalteon-Gi complex
Map data
Sample
  • Complex: melatonin receptor 2 with G peotein complex
    • Protein or peptide: Melatonin receptor type 1B
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: scFv16
  • Ligand: N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide
KeywordsG protein coupled receptor / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of circadian sleep/wake cycle, non-REM sleep / melatonin receptor activity / regulation of neuronal action potential / negative regulation of transmission of nerve impulse / positive regulation of transmission of nerve impulse / camera-type eye development / Class A/1 (Rhodopsin-like receptors) / G-protein activation / Activation of the phototransduction cascade / Glucagon-type ligand receptors ...positive regulation of circadian sleep/wake cycle, non-REM sleep / melatonin receptor activity / regulation of neuronal action potential / negative regulation of transmission of nerve impulse / positive regulation of transmission of nerve impulse / camera-type eye development / Class A/1 (Rhodopsin-like receptors) / 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 / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Ca2+ pathway / G alpha (z) signalling events / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Adrenaline,noradrenaline inhibits insulin secretion / ADP signalling through P2Y purinoceptor 12 / G alpha (q) signalling events / G alpha (i) signalling events / Thrombin signalling through proteinase activated receptors (PARs) / photoreceptor outer segment membrane / negative regulation of vasoconstriction / negative regulation of cytosolic calcium ion concentration / negative regulation of cGMP-mediated signaling / spectrin binding / alkylglycerophosphoethanolamine phosphodiesterase activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / photoreceptor outer segment / negative regulation of insulin secretion / positive regulation of protein localization to cell cortex / Adenylate cyclase inhibitory pathway / T cell migration / D2 dopamine receptor binding / response to prostaglandin E / G protein-coupled serotonin receptor binding / adenylate cyclase regulator activity / adenylate cyclase-inhibiting serotonin receptor signaling pathway / photoreceptor inner segment / cardiac muscle cell apoptotic process / cellular response to forskolin / regulation of insulin secretion / regulation of mitotic spindle organization / Regulation of insulin secretion / positive regulation of cholesterol biosynthetic process / G protein-coupled receptor binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G protein-coupled receptor activity / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / response to peptide hormone / G-protein beta/gamma-subunit complex binding / centriolar satellite / ADP signalling through P2Y purinoceptor 12 / Adrenaline,noradrenaline inhibits insulin secretion / GDP binding / G alpha (z) signalling events / ADORA2B mediated anti-inflammatory cytokines production / GPER1 signaling / glucose homeostasis / heterotrimeric G-protein complex / sensory perception of taste / signaling receptor complex adaptor activity / G protein activity / cell body / GTPase binding / positive regulation of cytosolic calcium ion concentration / retina development in camera-type eye / midbody / cell cortex / G alpha (i) signalling events / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / chemical synaptic transmission / cellular response to hypoxia / negative regulation of neuron apoptotic process / Extra-nuclear estrogen signaling / cell population proliferation / ciliary basal body / G protein-coupled receptor signaling pathway / lysosomal membrane / cell division / GTPase activity / synapse / centrosome / dendrite / protein-containing complex binding / GTP binding / nucleolus / magnesium ion binding / Golgi apparatus / extracellular exosome / nucleoplasm / plasma membrane
Similarity search - Function
Melatonin receptor family / Melatonin receptor 1A/1B / 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 / Guanine nucleotide-binding protein, beta subunit ...Melatonin receptor family / Melatonin receptor 1A/1B / 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 / 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. / WD domain, G-beta repeat / 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
Melatonin receptor type 1B / Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Rattus norvegicus (Norway rat)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.46 Å
AuthorsWang QG / Lu QY
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Nat Commun / Year: 2022
Title: Structural basis of the ligand binding and signaling mechanism of melatonin receptors.
Authors: Qinggong Wang / Qiuyuan Lu / Qiong Guo / Maikun Teng / Qingguo Gong / Xu Li / Yang Du / Zheng Liu / Yuyong Tao /
Abstract: Melatonin receptors (MT and MT in humans) are family A G protein-coupled receptors that respond to the neurohormone melatonin to regulate circadian rhythm and sleep. Numerous efforts have been made ...Melatonin receptors (MT and MT in humans) are family A G protein-coupled receptors that respond to the neurohormone melatonin to regulate circadian rhythm and sleep. Numerous efforts have been made to develop drugs targeting melatonin receptors for the treatment of insomnia, circadian rhythm disorder, and cancer. However, designing subtype-selective melatonergic drugs remains challenging. Here, we report the cryo-EM structures of the MT-G signaling complex with 2-iodomelatonin and ramelteon and the MT-G signaling complex with ramelteon. These structures, together with the reported functional data, reveal that although MT and MT possess highly similar orthosteric ligand-binding pockets, they also display distinctive features that could be targeted to design subtype-selective drugs. The unique structural motifs in MT and MT mediate structural rearrangements with a particularly wide opening on the cytoplasmic side. G is engaged in the receptor core shared by MT and MT and presents a conformation deviating from those in other G complexes. Together, our results provide new clues for designing melatonergic drugs and further insights into understanding the G protein coupling mechanism.
History
DepositionSep 20, 2021-
Header (metadata) releaseMar 2, 2022-
Map releaseMar 2, 2022-
UpdateNov 6, 2024-
Current statusNov 6, 2024Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.13
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.13
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7vh0
  • Surface level: 0.13
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

emd_31982.png

Downloads & links

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Map

FileDownload / File: emd_31982.map.gz / Format: CCP4 / Size: 64 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å		0.85 Å/pix.
x 256 pix.
= 217.6 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 0.85 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.13 / Movie #1: 0.13
Minimum - Maximum-0.7275918 - 1.0439599
Average (Standard dev.)0.00007914922 (±0.029584885)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions256256256
Spacing256256256
CellA=B=C: 217.6 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z0.850.850.85
M x/y/z256256256
origin x/y/z0.0000.0000.000
length x/y/z217.600217.600217.600
α/β/γ90.00090.00090.000
start NX/NY/NZ139118109
NX/NY/NZ123164187
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS256256256
D min/max/mean-0.7281.0440.000

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Supplemental data

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Sample components

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Entire : melatonin receptor 2 with G peotein complex

EntireName: melatonin receptor 2 with G peotein complex
Components
  • Complex: melatonin receptor 2 with G peotein complex
    • Protein or peptide: Melatonin receptor type 1B
    • Protein or peptide: Guanine nucleotide-binding protein G(i) subunit alpha-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: scFv16
  • Ligand: N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide

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Supramolecule #1: melatonin receptor 2 with G peotein complex

SupramoleculeName: melatonin receptor 2 with G peotein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Melatonin receptor type 1B

MacromoleculeName: Melatonin receptor type 1B / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.308285 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MSENGSFANC CEAGGWAVRP GWSGAGSARP SRTPRPPWVA PALSAVLIVT TAVDVVGNLL VILSVLRNRK LRNAGNLFLV SLALADLVV AFYPYPLILV AIFYDGWAFG EEHCKASAFV MGLSVIGSVW NITAIAINRY LYICHSMAYH RIYRRWHTPL H ICLIWLLT ...String:
MSENGSFANC CEAGGWAVRP GWSGAGSARP SRTPRPPWVA PALSAVLIVT TAVDVVGNLL VILSVLRNRK LRNAGNLFLV SLALADLVV AFYPYPLILV AIFYDGWAFG EEHCKASAFV MGLSVIGSVW NITAIAINRY LYICHSMAYH RIYRRWHTPL H ICLIWLLT VVALLPNFFV GSLEYDPRIY SCTFIQTAST QYTAAVVVIH FLLPIAVVSF CYLRIWVLVL QARRKAKPES RL CLKPSDL RSFLTMFVVF VIFAICWAPL NCIGLAVAIN PQEMAPQIPE GLFVTSYLLA YFNSCLNAIV YGLLNQNFRR EYK RILLAL WNPRHCIQDA SKGSHAEGLQ SPAPPIIGVQ HQADAL

UniProtKB: Melatonin receptor type 1B

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Macromolecule #2: Guanine nucleotide-binding protein G(i) subunit alpha-1

MacromoleculeName: Guanine nucleotide-binding protein G(i) subunit alpha-1
type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 40.340887 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String:
GGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA TDTKNVQFVF DAVTDVIIKN NLKDCGLF

UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Rattus norvegicus (Norway rat)
Molecular weightTheoretical: 39.021648 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: HHHHHHHHMG SLLQSELDEL RQEAEQLKNQ IRDARKACAD ATLSQITNNI DPVGRIQMRT RRTLRGHLAK IYAMHWGTDS RLLVSASQD GKLIIWDSYT TNKVHAIPLR SSWVMTCAYA PSGNYVACGG LDNICSIYNL KTRQGNVRVS RELAGHTGYL S CCRFLDDN ...String:
HHHHHHHHMG SLLQSELDEL RQEAEQLKNQ IRDARKACAD ATLSQITNNI DPVGRIQMRT RRTLRGHLAK IYAMHWGTDS RLLVSASQD GKLIIWDSYT TNKVHAIPLR SSWVMTCAYA PSGNYVACGG LDNICSIYNL KTRQGNVRVS RELAGHTGYL S CCRFLDDN QIVTSSGDTT CALWDIETGQ QTTTFTGHTG DVMSLSLAPD TRLFVSGACD ASAKLWDVRE GMCRQTFTGH ES DINAICF FPDGNAFATG SDDATCRLFD LRADQELMTY SHDNIICGIT SVSFSKSGRL LLAGYDDFNC NVWDALKADR AGV LAGHDN RVSCLGVTDD GMAVATGSWD SFLKIWN

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #4: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 4 / Number of copies: 2 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 34.767035 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: ASNNTASIAQ ARKLVQQLKM EANIDRIKVS KAAADLMAYC EAHAKEDPLL TPVPASQNPF REKKFFCDVQ LVESGGGLVQ PGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA M YYCVRSIY ...String:
ASNNTASIAQ ARKLVQQLKM EANIDRIKVS KAAADLMAYC EAHAKEDPLL TPVPASQNPF REKKFFCDVQ LVESGGGLVQ PGGSRKLSC SASGFAFSSF GMHWVRQAPE KGLEWVAYIS SGSGTIYYAD TVKGRFTISR DDPKNTLFLQ MTSLRSEDTA M YYCVRSIY YYGSSPFDFW GQGTTLTVSS GGGGSGGGGS GGGGSDIVMT QATSSVPVTP GESVSISCRS SKSLLHSNGN TY LYWFLQR PGQSPQLLIY RMSNLASGVP ERFSGSGSGT AFTLTISRLE AEDVGVYYCM QHLEYPLTFG AGTKLELKGS LEV LFQ

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Macromolecule #5: N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}pr...

MacromoleculeName: N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide
type: ligand / ID: 5 / Number of copies: 1 / Formula: JEV
Molecular weightTheoretical: 259.343 Da
Chemical component information

ChemComp-JEV:
N-{2-[(8S)-1,6,7,8-tetrahydro-2H-indeno[5,4-b]furan-8-yl]ethyl}propanamide / medication, agonist*YM

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation state2D array

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: OTHER

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.0 µm / Nominal defocus min: 1.2 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

6me9

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.46 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 335170
Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION

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