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- PDB-7e2z: Aripiprazole-bound serotonin 1A (5-HT1A) receptor-Gi protein complex -

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Basic information

Entry
Database: PDB / ID: 7e2z
TitleAripiprazole-bound serotonin 1A (5-HT1A) receptor-Gi protein complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Soluble cytochrome b562,5-hydroxytryptamine receptor 1A
KeywordsSIGNALING PROTEIN / Serotonin / 5-HT1A / GPCR / Complex / G protein / Gi / aripiprazole
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 / regulation of mitotic spindle organization / G protein-coupled acetylcholine receptor signaling pathway / regulation of cAMP-mediated signaling / G-protein beta/gamma-subunit complex / neurotransmitter receptor activity / cellular response to catecholamine stimulus / G-protein gamma-subunit binding / 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
GGL domain / G-protein gamma-like domain / G protein-coupled receptor, rhodopsin-like / 5-Hydroxytryptamine 1A receptor / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit, group I / G-protein, beta subunit / WD40 repeat / G-protein, gamma subunit / Cytochrome b562 ...GGL domain / G-protein gamma-like domain / G protein-coupled receptor, rhodopsin-like / 5-Hydroxytryptamine 1A receptor / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit, group I / G-protein, beta subunit / WD40 repeat / G-protein, gamma subunit / Cytochrome b562 / Cytochrome c/b562 / G protein alpha subunit, helical insertion / 5-hydroxytryptamine receptor family / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase / WD domain, G-beta repeat / Guanine nucleotide-binding protein, beta subunit / G-protein gamma-like domain superfamily / WD40-repeat-containing domain superfamily / G-protein beta WD-40 repeat / WD40 repeat, conserved site / WD40-repeat-containing domain / GPCR, rhodopsin-like, 7TM
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)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.1 Å
AuthorsXu, P. / Huang, S. / Zhang, H. / Mao, C. / Zhou, X.E. / Shen, D.D. / Jiang, Y. / Zhang, Y. / Xu, H.E.
Funding support China, 1items
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 Report
SummaryFull reportAbout validation report
History
DepositionFeb 7, 2021Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1Apr 28, 2021Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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Structure visualization

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Assembly

Deposited unit
A: Guanine nucleotide-binding protein G(i) subunit alpha-1
B: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A
hetero molecules


Theoretical massNumber of molelcules
Total (without water)149,0629
Polymers146,5994
Non-polymers2,4635
Water0
1


TypeNameSymmetry operationNumber
identity operation1_5551

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Components

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

#1: Protein Guanine nucleotide-binding protein G(i) subunit alpha-1 / Adenylate cyclase-inhibiting G alpha protein


Mass: 40414.047 Da / Num. of mol.: 1 / Mutation: S47N, G203A, E245A, A326S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: GNAI1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P63096
#2: Protein Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 / Transducin beta chain 1


Mass: 37915.496 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
#3: 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.) Homo sapiens (human) / Gene: GNG2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P59768

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Protein , 1 types, 1 molecules R

#4: Protein Soluble cytochrome b562,5-hydroxytryptamine receptor 1A / Cytochrome b-562 / 5-HT-1A / 5-HT1A / G-21 / Serotonin receptor 1A


Mass: 60408.512 Da / Num. of mol.: 1 / Mutation: M7W,H102I,R106L,L125W
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, HTR1A, ADRB2RL1, ADRBRL1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: P08908

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Non-polymers , 3 types, 5 molecules

#5: Chemical ChemComp-9SC / 7-[4-[4-[2,3-bis(chloranyl)phenyl]piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one / Aripiprazole / Aripiprazole


Mass: 448.385 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27Cl2N3O2 / Feature type: SUBJECT OF INVESTIGATION / Comment: antipsychotic*YM
#6: Chemical ChemComp-CLR / CHOLESTEROL / Cholesterol


Mass: 386.654 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C27H46O
#7: Chemical ChemComp-J40 / [(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


Mass: 854.895 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C39H68O16P2

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Details

Has ligand of interestY

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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: Aripiprazole-bound Serotonin 1A (5-HT1A) receptor-Gi protein complex
Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
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 / Humidity: 100 % / Chamber temperature: 277 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: FEI TITAN KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELDBright-field microscopy / Nominal magnification: 29000 X / Calibrated magnification: 49310 X / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 62 e/Å2 / Detector mode: COUNTING / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

SoftwareName: PHENIX / Version: 1.18.2_3874: / Classification: refinement
CTF correctionType: NONE
Particle selectionNum. of particles selected: 1486169
3D reconstructionResolution: 3.1 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 154241 / Symmetry type: POINT
Refine LS restraints
Refinement-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.0027142
ELECTRON MICROSCOPYf_angle_d0.4599682
ELECTRON MICROSCOPYf_dihedral_angle_d23.7471013
ELECTRON MICROSCOPYf_chiral_restr0.0381117
ELECTRON MICROSCOPYf_plane_restr0.0031188

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