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- PDB-7e33: Serotonin 1E (5-HT1E) receptor-Gi protein complex -

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Basic information

Entry
Database: PDB / ID: 7.0E+33
TitleSerotonin 1E (5-HT1E) receptor-Gi protein complex
Components
  • (Guanine nucleotide-binding protein ...) x 3
  • Soluble cytochrome b562,5-hydroxytryptamine receptor 1E
  • scFv16
KeywordsSIGNALING PROTEIN / Serotonin / 5-HT1e / BRL-54443 / GPCR / Complex / G protein / Gi
Function / homology
Function and homology information


adenylate cyclase-inhibiting serotonin receptor signaling pathway / Serotonin receptors / G protein-coupled serotonin receptor activity / serotonin binding / Adenylate cyclase inhibitory pathway / PLC beta mediated events / positive regulation of protein localization to cell cortex / G protein-coupled serotonin receptor binding / cell cortex region / Olfactory Signaling Pathway ...adenylate cyclase-inhibiting serotonin receptor signaling pathway / Serotonin receptors / G protein-coupled serotonin receptor activity / serotonin binding / Adenylate cyclase inhibitory pathway / 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 / cardiac muscle cell apoptotic process / regulation of mitotic spindle organization / 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 / G-protein gamma-subunit binding / cellular response to forskolin / cellular response to catecholamine stimulus / 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 / G protein-coupled receptor activity / 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 / dendrite / GTP binding / protein-containing complex binding
Similarity search - Function
5-Hydroxytryptamine 1E 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 1E 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 subunit-like motifs / G-protein gamma-like domain / GGL domain / Cytochrome c/b562 / G-alpha domain profile. / G-protein alpha subunit / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (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 receptors family 1 profile. / G protein-coupled receptor, rhodopsin-like / 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
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 / 3-(1-methylpiperidin-4-yl)-1H-indol-5-ol / 5-hydroxytryptamine receptor 1E / Soluble cytochrome b562 / Guanine nucleotide-binding protein G(i) subunit alpha-1
Similarity search - Component
Biological speciesHomo sapiens (human)
Mus musculus (house mouse)
Escherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.9 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.
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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  • Deposited structure unit
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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
E: scFv16
G: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
R: Soluble cytochrome b562,5-hydroxytryptamine receptor 1E
hetero molecules


Theoretical massNumber of molelcules
Total (without water)170,4166
Polymers170,1865
Non-polymers2301
Water0
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
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
#4: 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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Antibody / Protein / Non-polymers , 3 types, 3 molecules ER

#3: Antibody scFv16


Mass: 26466.486 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Production host: Spodoptera frugiperda (fall armyworm)
#5: Protein Soluble cytochrome b562,5-hydroxytryptamine receptor 1E / Cytochrome b-562 / 5-HT-1E / 5-HT1E / S31 / Serotonin receptor 1E


Mass: 57528.371 Da / Num. of mol.: 1 / Mutation: M7W,H102I,R106L,L111W
Source method: isolated from a genetically manipulated source
Details: The BRIL (soluble cytochrome b562) protein was used as the expression tag
Source: (gene. exp.) Escherichia coli (E. coli), (gene. exp.) Homo sapiens (human)
Gene: cybC, HTR1E / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P0ABE7, UniProt: P28566
#6: Chemical ChemComp-HVU / 3-(1-methylpiperidin-4-yl)-1H-indol-5-ol / BRL-54443


Mass: 230.306 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H18N2O / Feature type: SUBJECT OF INVESTIGATION / Comment: agonist*YM

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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

Component
IDNameTypeEntity IDParent-IDSource
1Serotonin 1E (5-HT1E) receptor-Gi protein complexCOMPLEX#1-#50MULTIPLE SOURCES
2receptor-Gi proteinCOMPLEX#1-#2, #4-#51RECOMBINANT
3scFv16COMPLEX#31RECOMBINANT
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
12Homo sapiens (human)9606
23Mus musculus (house mouse)10090
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
12Spodoptera frugiperda (fall armyworm)7108
23Spodoptera frugiperda (fall armyworm)7108
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

CTF correctionType: NONE
Particle selectionNum. of particles selected: 1486169
3D reconstructionResolution: 2.9 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 163354 / Symmetry type: POINT

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