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- EMDB-30971: Apo serotonin 1A (5-HT1A) receptor-Gi protein complex -

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Basic information

Entry
Database: EMDB / ID: EMD-30971
TitleApo serotonin 1A (5-HT1A) receptor-Gi protein complex
Map data
SampleApo serotonin 1A (5-HT1A) receptor-Gi protein complex
  • (Guanine nucleotide-binding protein ...) x 3
  • Soluble cytochrome b562,5-hydroxytryptamine receptor 1A
  • (ligand) x 4
Function / homology
Function and homology information


regulation of serotonin secretion / serotonin receptor signaling pathway / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / regulation of dopamine metabolic process / G protein-coupled serotonin receptor activity / exploration behavior / serotonin binding / receptor-receptor interaction ...regulation of serotonin secretion / serotonin receptor signaling pathway / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / regulation of dopamine metabolic process / G protein-coupled serotonin receptor activity / exploration behavior / serotonin binding / receptor-receptor interaction / gamma-aminobutyric acid signaling pathway / serotonin metabolic process / G protein-coupled serotonin receptor binding / positive regulation of protein localization to cell cortex / cell cortex region / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of vasoconstriction / cardiac muscle cell apoptotic process / sensory perception of taste / G protein-coupled acetylcholine receptor signaling pathway / regulation of mitotic spindle organization / regulation of cAMP-mediated signaling / G-protein beta/gamma-subunit complex / neurotransmitter receptor activity / G-protein gamma-subunit binding / cellular response to catecholamine stimulus / alkylglycerophosphoethanolamine phosphodiesterase activity / cellular response to forskolin / negative regulation of synaptic transmission / rhodopsin mediated signaling pathway / adenylate cyclase-activating dopamine receptor signaling pathway / photoreceptor outer segment membrane / positive regulation of potassium ion transmembrane transport / G-protein beta-subunit binding / photoreceptor disc membrane / spectrin binding / G-protein beta/gamma-subunit complex binding / GTPase activating protein binding / heterotrimeric G-protein complex / behavioral fear response / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / extracellular vesicle / Wnt signaling pathway, calcium modulating pathway / cellular response to prostaglandin E stimulus / 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 / photoreceptor inner segment / GDP binding / cell population proliferation / cell body / midbody / negative regulation of inflammatory response to antigenic stimulus / lysosomal membrane / positive regulation of cytosolic calcium ion concentration / cellular response to hypoxia / Ras protein signal transduction / chemical synaptic transmission / platelet activation / protein folding / cell cycle / periplasmic space / electron transfer activity / GTPase activity / iron ion binding / cell division / centrosome / synapse / G protein-coupled receptor signaling pathway / membrane raft / dendrite / GTP binding / protein-containing complex binding / heme binding / positive regulation of cell population proliferation / magnesium ion binding / signal transduction / integral component of plasma membrane / extracellular exosome / membrane / plasma membrane / nucleus / cytosol / cytoplasm
G-protein gamma-like domain / Guanine nucleotide binding protein (G-protein), alpha subunit / GPCR, rhodopsin-like, 7TM / WD40/YVTN repeat-like-containing domain superfamily / WD40-repeat-containing domain / Guanine nucleotide-binding protein, beta subunit / G protein-coupled receptor, rhodopsin-like / WD40 repeat, conserved site / G-protein beta WD-40 repeat / 5-Hydroxytryptamine 1A receptor ...G-protein gamma-like domain / Guanine nucleotide binding protein (G-protein), alpha subunit / GPCR, rhodopsin-like, 7TM / WD40/YVTN repeat-like-containing domain superfamily / WD40-repeat-containing domain / Guanine nucleotide-binding protein, beta subunit / G protein-coupled receptor, rhodopsin-like / WD40 repeat, conserved site / G-protein beta WD-40 repeat / 5-Hydroxytryptamine 1A receptor / P-loop containing nucleoside triphosphate hydrolase / G-protein alpha subunit, group I / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / G-protein, beta subunit / WD40 repeat / G-protein, gamma subunit / 5-hydroxytryptamine receptor family / Cytochrome b562 / Cytochrome c/b562 / G protein alpha subunit, helical insertion
5-hydroxytryptamine receptor 1A / 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 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3 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.
Validation ReportSummary, Full report, XML, About validation report
History
DepositionFeb 7, 2021-
Header (metadata) releaseApr 14, 2021-
Map releaseApr 14, 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: 0.03
  • Imaged by UCSF Chimera
  • Download
  • Surface view colored by height
  • Surface level: 0.03
  • Imaged by UCSF Chimera
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  • Surface view with fitted model
  • Atomic models: PDB-7e2x
  • Surface level: 0.03
  • 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_30971.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.)
1.01 Å/pix.
x 192 pix.
= 194.688 Å
1.01 Å/pix.
x 192 pix.
= 194.688 Å
1.01 Å/pix.
x 192 pix.
= 194.688 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.014 Å
Density
Contour LevelBy AUTHOR: 0.03 / Movie #1: 0.03
Minimum - Maximum-0.18254171 - 0.25767928
Average (Standard dev.)-0.00015126685 (±0.008018867)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions192192192
Spacing192192192
CellA=B=C: 194.68802 Å
α=β=γ: 90.0 °

CCP4 map header:

modeImage stored as Reals
Å/pix. X/Y/Z1.0141.0141.014
M x/y/z192192192
origin x/y/z0.0000.0000.000
length x/y/z194.688194.688194.688
α/β/γ90.00090.00090.000
start NX/NY/NZ000
NX/NY/NZ256256256
MAP C/R/S123
start NC/NR/NS000
NC/NR/NS192192192
D min/max/mean-0.1830.258-0.000

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Supplemental data

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Sample components

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Entire Apo serotonin 1A (5-HT1A) receptor-Gi protein complex

EntireName: Apo serotonin 1A (5-HT1A) receptor-Gi protein complex / Number of components: 9

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Component #1: protein, Apo serotonin 1A (5-HT1A) receptor-Gi protein complex

ProteinName: Apo serotonin 1A (5-HT1A) receptor-Gi protein complex / Recombinant expression: No
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #2: 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 #3: 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 #4: 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 #5: protein, Soluble cytochrome b562,5-hydroxytryptamine receptor 1A

ProteinName: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A
Details: The BRIL (soluble cytochrome b562) protein was used as the expression tag.
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 60.408512 kDa
SourceSpecies: Homo sapiens (human)
Source (engineered)Expression System: Spodoptera frugiperda (fall armyworm)

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Component #6: ligand, [(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidany...

LigandName: [(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-phosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-3-tetradecanoyloxy-propan-2-yl] (5E,8E)-hexadeca-5,8,11,14-tetraenoate
Number of Copies: 1 / Recombinant expression: No
MassTheoretical: 0.854895 kDa

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Component #7: ligand, CHOLESTEROL

LigandName: CHOLESTEROL / Number of Copies: 10 / Recombinant expression: No
MassTheoretical: 0.386654 kDa

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Component #8: ligand, PALMITIC ACID

LigandName: PALMITIC ACID / Number of Copies: 3 / Recombinant expression: No
MassTheoretical: 0.256424 kDa

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Component #9: ligand, water

LigandName: water / Number of Copies: 9 / Recombinant expression: No
MassTheoretical: 1.801505 MDa

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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: 62 e/Å2 / Illumination mode: FLOOD BEAM
LensMagnification: 29000 X (nominal), 49310 X (calibrated) / Cs: 2.7 mm / Imaging mode: BRIGHT FIELD
Specimen HolderModel: FEI TITAN KRIOS AUTOGRID HOLDER
CameraDetector: GATAN K2 SUMMIT (4k x 4k)

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Image processing

ProcessingMethod: single particle reconstruction / Number of projections: 245886
3D reconstructionResolution: 3 Å / Resolution method: FSC 0.143 CUT-OFF

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Atomic model buiding

Output model

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