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- EMDB-30974: Serotonin 1D (5-HT1D) receptor-Gi protein complex -

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Basic information

Entry
Database: EMDB / ID: EMD-30974
TitleSerotonin 1D (5-HT1D) receptor-Gi protein complex
Map data
SampleSerotonin 1D (5-HT1D) receptor-Gi protein complex
  • receptor-Gi protein
  • (scFv16) x 2
  • (Guanine nucleotide-binding protein ...) x 3
  • Soluble cytochrome b562,5-hydroxytryptamine receptor 1D
  • (ligand) x 2
Function / homology
Function and homology information


intestine smooth muscle contraction / adenylate cyclase-inhibiting serotonin receptor signaling pathway / Serotonin receptors / regulation of behavior / regulation of locomotion / G protein-coupled serotonin receptor activity / serotonin binding / Adenylate cyclase inhibitory pathway / vasoconstriction / PLC beta mediated events ...intestine smooth muscle contraction / adenylate cyclase-inhibiting serotonin receptor signaling pathway / Serotonin receptors / regulation of behavior / regulation of locomotion / G protein-coupled serotonin receptor activity / serotonin binding / Adenylate cyclase inhibitory pathway / vasoconstriction / PLC beta mediated events / positive regulation of protein localization to cell cortex / G protein-coupled serotonin receptor binding / cell cortex region / Olfactory Signaling Pathway / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / Thromboxane signalling through TP receptor / Presynaptic function of Kainate receptors / G beta:gamma signalling through PLC beta / Activation of the phototransduction cascade / Prostacyclin signalling through prostacyclin receptor / ADP signalling through P2Y purinoceptor 12 / G-protein activation / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Activation of G protein gated Potassium channels / Adrenaline,noradrenaline inhibits insulin secretion / Glucagon signaling in metabolic regulation / regulation of mitotic spindle organization / cardiac muscle cell apoptotic process / regulation of cAMP-mediated signaling / G protein-coupled acetylcholine receptor signaling pathway / sensory perception of taste / neurotransmitter receptor activity / G-protein beta/gamma-subunit complex / cellular response to catecholamine stimulus / G-protein gamma-subunit binding / cellular response to forskolin / G beta:gamma signalling through CDC42 / alkylglycerophosphoethanolamine phosphodiesterase activity / G alpha (z) signalling events / negative regulation of synaptic transmission / rhodopsin mediated signaling pathway / Glucagon-type ligand receptors / G beta:gamma signalling through BTK / adenylate cyclase-activating dopamine receptor signaling pathway / Vasopressin regulates renal water homeostasis via Aquaporins / photoreceptor outer segment membrane / photoreceptor disc membrane / positive regulation of potassium ion transmembrane transport / G-protein beta-subunit binding / spectrin binding / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G-protein beta/gamma-subunit complex binding / GTPase activating protein binding / heterotrimeric G-protein complex / G beta:gamma signalling through PI3Kgamma / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / Regulation of insulin secretion / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / Wnt signaling pathway, calcium modulating pathway / cellular response to prostaglandin E stimulus / G alpha (12/13) signalling events / ADORA2B mediated anti-inflammatory cytokines production / phospholipase C-activating G protein-coupled receptor signaling pathway / response to peptide hormone / G protein-coupled receptor binding / retina development in camera-type eye / GTPase binding / Ca2+ pathway / Thrombin signalling through proteinase activated receptors (PARs) / photoreceptor inner segment / G alpha (s) signalling events / G alpha (i) signalling events / GDP binding / G alpha (q) signalling events / cell population proliferation / cell body / midbody / lysosomal membrane / negative regulation of inflammatory response to antigenic stimulus / Extra-nuclear estrogen signaling / cellular response to hypoxia / positive regulation of cytosolic calcium ion concentration / Ras protein signal transduction / chemical synaptic transmission / platelet activation / protein folding / cell cycle / periplasmic space / electron transfer activity / GTPase activity / iron ion binding / centrosome / cell division / synapse / G protein-coupled receptor signaling pathway / membrane raft
Similarity search - Function
5-Hydroxytryptamine 1D receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group I / Cytochrome b562 / Cytochrome b562 / G-protein gamma subunit domain profile. / G-protein, gamma subunit / Guanine nucleotide-binding protein, beta subunit / G-protein gamma-like domain superfamily / G-protein, beta subunit ...5-Hydroxytryptamine 1D receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group I / Cytochrome b562 / Cytochrome b562 / G-protein gamma subunit domain profile. / G-protein, gamma subunit / Guanine nucleotide-binding protein, beta subunit / G-protein gamma-like domain superfamily / G-protein, beta subunit / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / Cytochrome c/b562 / G-alpha domain profile. / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / GPCR, rhodopsin-like, 7TM / G protein-coupled receptor, rhodopsin-like / G-protein coupled receptors family 1 profile. / 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-repeat-containing domain / 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
Soluble cytochrome b562 / 5-hydroxytryptamine receptor 1D / 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 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.9 Å
AuthorsXu P / Huang S / Zhang H / Mao C / Zhou XE / Shen DD / Jiang Y / Zhang Y / Xu HE
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)31770796 China
CitationJournal: Nature / Year: 2021
Title: Structural insights into the lipid and ligand regulation of serotonin receptors.
Authors: Peiyu Xu / Sijie Huang / Huibing Zhang / Chunyou Mao / X Edward Zhou / Xi Cheng / Icaro A Simon / Dan-Dan Shen / Hsin-Yung Yen / Carol V Robinson / Kasper Harpsøe / Bo Svensson / Jia Guo / ...Authors: Peiyu Xu / Sijie Huang / Huibing Zhang / Chunyou Mao / X Edward Zhou / Xi Cheng / Icaro A Simon / Dan-Dan Shen / Hsin-Yung Yen / Carol V Robinson / Kasper Harpsøe / Bo Svensson / Jia Guo / Hualiang Jiang / David E Gloriam / Karsten Melcher / Yi Jiang / Yan Zhang / H Eric Xu /
Abstract: Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter that activates the largest subtype family of G-protein-coupled receptors. Drugs that target 5-HT, 5-HT, 5-HT and other 5-HT ...Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter that activates the largest subtype family of G-protein-coupled receptors. Drugs that target 5-HT, 5-HT, 5-HT and other 5-HT receptors are used to treat numerous disorders. 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor-G-protein complexes: 5-HT in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT bound to 5-HT; and 5-HT in complex with a 5-HT- and 5-HT-selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein-5-HT interface, and is able to increase 5-HT-mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules-particularly in the case of 5-HT, in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors.
History
DepositionFeb 7, 2021-
Header (metadata) releaseApr 21, 2021-
Map releaseApr 21, 2021-
UpdateApr 28, 2021-
Current statusApr 28, 2021Processing site: PDBj / Status: Released

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Structure visualization

Movie
  • Surface view with section colored by density value
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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  • Surface view colored by height
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7e32
  • Surface level: 0.06
  • Imaged by UCSF Chimera
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Movie viewer
Structure viewerEM map:
SurfViewMolmilJmol/JSmol
Supplemental images

Downloads & links

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Map

FileDownload / File: emd_30974.map.gz / Format: CCP4 / Size: 27 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.05 Å/pix.
x 192 pix.
= 200.64 Å
1.05 Å/pix.
x 192 pix.
= 200.64 Å
1.05 Å/pix.
x 192 pix.
= 200.64 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.045 Å
Density
Contour LevelBy AUTHOR: 0.06 / Movie #1: 0.06
Minimum - Maximum-0.3933584 - 0.6237884
Average (Standard dev.)-0.00012551222 (±0.015493338)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 200.63998 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0451.0451.045
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z200.640200.640200.640
α/β/γ90.00090.00090.000
start NX/NY/NZ1219875
NX/NY/NZ141223232
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-0.3930.624-0.000

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Supplemental data

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Sample components

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Entire Serotonin 1D (5-HT1D) receptor-Gi protein complex

EntireName: Serotonin 1D (5-HT1D) receptor-Gi protein complex / Number of components: 10

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Component #1: protein, Serotonin 1D (5-HT1D) receptor-Gi protein complex

ProteinName: Serotonin 1D (5-HT1D) receptor-Gi protein complex / Recombinant expression: No

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Component #2: protein, receptor-Gi protein

ProteinName: receptor-Gi protein / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #3: protein, scFv16

ProteinName: scFv16 / Recombinant expression: No
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #4: protein, Guanine nucleotide-binding protein G(i) subunit alpha-1

ProteinName: Guanine nucleotide-binding protein G(i) subunit alpha-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 40.414047 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #5: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(T) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 37.915496 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #6: protein, scFv16

ProteinName: scFv16 / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 26.466486 kDa
SourceSpecies: Mus musculus (house mouse)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #7: protein, Guanine nucleotide-binding protein G(I)/G(S)/G(O) subuni...

ProteinName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 7.861143 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #8: protein, Soluble cytochrome b562,5-hydroxytryptamine receptor 1D

ProteinName: Soluble cytochrome b562,5-hydroxytryptamine receptor 1D
Details: The BRIL (soluble cytochrome b562) protein was used as the expression tag
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 57.748188 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #9: ligand, SEROTONIN

LigandName: SEROTONIN / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.176215 kDa

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Component #10: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Experimental details

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Sample preparation

SpecimenSpecimen state: Particle / Method: cryo EM
Sample solutionpH: 7.4
VitrificationCryogen name: ETHANE / Temperature: 277 K / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
ImagingMicroscope: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Electron dose: 70 e/Å2 / Illumination mode: FLOOD BEAM
LensMagnification: 47847 X (calibrated) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: OTHER

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 141501
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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