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- EMDB-36409: ST1936-5HT6R complex -

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Entry
Database: EMDB / ID: EMD-36409
TitleST1936-5HT6R complex
Map dataThis is the cryo-EM density of ST1936-ht6 complex.
Sample
  • Complex: st1936-HT6
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nb35
    • Protein or peptide: 5-hydroxytryptamine receptor 65-HT receptor
  • Ligand: 2-(5-chloranyl-2-methyl-1~{H}-indol-3-yl)-N,N-dimethyl-ethanamine
KeywordsGPCR / MEMBRANE PROTEIN
Function / homology
Function and homology information


histamine receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / cerebral cortex cell migration / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / D1 dopamine receptor binding ...histamine receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / cerebral cortex cell migration / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / PKA activation in glucagon signalling / hair follicle placode formation / developmental growth / D1 dopamine receptor binding / positive regulation of TOR signaling / intracellular transport / Hedgehog 'off' state / positive regulation of cAMP-mediated signaling / adenylate cyclase-activating adrenergic receptor signaling pathway / activation of adenylate cyclase activity / adenylate cyclase activator activity / trans-Golgi network membrane / Olfactory Signaling Pathway / G-protein beta/gamma-subunit complex binding / Activation of the phototransduction cascade / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / bone development / G-protein activation / G protein-coupled acetylcholine receptor signaling pathway / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / cilium / Prostacyclin signalling through prostacyclin receptor / adenylate cyclase-activating G protein-coupled receptor signaling pathway / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / ADP signalling through P2Y purinoceptor 12 / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Adrenaline,noradrenaline inhibits insulin secretion / platelet aggregation / cognition / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of GTPase activity / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / adenylate cyclase-activating dopamine receptor signaling pathway / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / sensory perception of taste / GPER1 signaling / G-protein beta-subunit binding / Inactivation, recovery and regulation of the phototransduction cascade / heterotrimeric G-protein complex / G alpha (12/13) signalling events / extracellular vesicle / signaling receptor complex adaptor activity / sensory perception of smell / Thrombin signalling through proteinase activated receptors (PARs) / retina development in camera-type eye / GTPase binding / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / positive regulation of cold-induced thermogenesis / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / chemical synaptic transmission / G alpha (q) signalling events / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / dendrite / synapse / protein-containing complex binding / GTP binding / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytosol / cytoplasm
Similarity search - Function
5-Hydroxytryptamine 6 receptor / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. ...5-Hydroxytryptamine 6 receptor / G-protein alpha subunit, group S / Serpentine type 7TM GPCR chemoreceptor Srsx / G-alpha domain profile. / Guanine nucleotide binding protein (G-protein), alpha subunit / G protein alpha subunit, helical insertion / G-protein alpha subunit / G protein alpha subunit / G-protein, gamma subunit / G-protein gamma subunit domain profile. / GGL domain / G-protein gamma-like domain superfamily / G-protein gamma-like domain / GGL domain / G protein gamma subunit-like motifs / 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 / WD40 repeats / WD40 repeat / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
5-hydroxytryptamine receptor 6 / 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(s) subunit alpha isoforms short
Similarity search - Component
Biological speciesHomo sapiens (human) / Camelus bactrianus (Bactrian camel)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.09 Å
AuthorsWen X / Sun J
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC) China
CitationJournal: Biochem Biophys Res Commun / Year: 2023
Title: Structural insight into the selective agonist ST1936 binding of serotonin receptor 5-HT6.
Authors: Yuan Pei / Xin Wen / Sheng-Chao Guo / Zhi-Shuai Yang / Ru Zhang / Peng Xiao / Jin-Peng Sun /
Abstract: The serotonin receptor 5-HTR is an important G-protein-coupled receptor (GPCR) that involved in essential functions within the central and peripheral nervous systems and is linked to various ...The serotonin receptor 5-HTR is an important G-protein-coupled receptor (GPCR) that involved in essential functions within the central and peripheral nervous systems and is linked to various psychiatric disorders. Selective activation of 5-HTR promotes neural stem cell regeneration activity. As a 5-HTR selective agonist, 2-(5 chloro-2-methyl-1H-indol-3-yl)-N, N-dimethylethanolamine (ST1936) has been widely used to investigate the functions of the 5-HTR. The molecular mechanism of how ST1936 is recognized by 5-HTR and how it effectively couples with Gs remain unclear. Here, we reconstituted the ST1936-5-HTR-Gs complex in vitro and solved its cryo-electron microscopy structure at 3.1 Å resolution. Further structural analysis and mutational studies facilitated us to identify the residues of the Y310 and "toggle switch" W281 of the 5-HTR contributed to the higher efficacy of ST1936 compared with 5-HT. By uncovering the structural foundation of how 5-HTR specifically recognizes agonists and elucidating the molecular process of G protein activation, our discoveries offer valuable insights and pave the way for the development of promising 5-HTR agonists.
History
DepositionJun 4, 2023-
Header (metadata) releaseJun 28, 2023-
Map releaseJun 28, 2023-
UpdateJun 28, 2023-
Current statusJun 28, 2023Processing site: PDBj / Status: Released

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Structure visualization

Supplemental images

emd_36409.png

Downloads & links

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Map

FileDownload / File: emd_36409.map.gz / Format: CCP4 / Size: 30.5 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationThis is the cryo-EM density of ST1936-ht6 complex.
Voxel sizeX=Y=Z: 0.85 Å
Density
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.0018105257 - 2.3484554
Average (Standard dev.)0.0041954922 (±0.050170623)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions200200200
Spacing200200200
CellA=B=C: 170.0 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: This is the half1 map.

Fileemd_36409_half_map_1.map
AnnotationThis is the half1 map.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: This is the half2 map.

Fileemd_36409_half_map_2.map
AnnotationThis is the half2 map.
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : st1936-HT6

EntireName: st1936-HT6
Components
  • Complex: st1936-HT6
    • Protein or peptide: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: Nb35
    • Protein or peptide: 5-hydroxytryptamine receptor 65-HT receptor
  • Ligand: 2-(5-chloranyl-2-methyl-1~{H}-indol-3-yl)-N,N-dimethyl-ethanamine

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Supramolecule #1: st1936-HT6

SupramoleculeName: st1936-HT6 / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short

MacromoleculeName: Guanine nucleotide-binding protein G(s) subunit alpha isoforms short
type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 45.683434 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE ...String:
MGCLGNSKTE DQRNEEKAQR EANKKIEKQL QKDKQVYRAT HRLLLLGAGE SGKNTIVKQM RILHVNGFNG EGGEEDPQAA RSNSDGEKA TKVQDIKNNL KEAIETIVAA MSNLVPPVEL ANPENQFRVD YILSVMNVPD FDFPPEFYEH AKALWEDEGV R ACYERSNE YQLIDCAQYF LDKIDVIKQA DYVPSDQDLL RCRVLTSGIF ETKFQVDKVN FHMFDVGAQR DERRKWIQCF ND VTAIIFV VASSSYNMVI REDNQTNRLQ AALKLFDSIW NNKWLRDTSV ILFLNKQDLL AEKVLAGKSK IEDYFPEFAR YTT PEDATP EPGEDPRVTR AKYFIRDEFL RISTASGDGR HYCYPHFTCA VDTENIRRVF NDCRDIIQRM HLRQYELL

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Macromolecule #2: 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: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.418086 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR ...String:
MHHHHHHLEV LFQGPGSSGS ELDQLRQEAE QLKNQIRDAR KACADATLSQ ITNNIDPVGR IQMRTRRTLR GHLAKIYAMH WGTDSRLLV SASQDGKLII WDSYTTNKVH AIPLRSSWVM TCAYAPSGNY VACGGLDNIC SIYNLKTREG NVRVSRELAG H TGYLSCCR FLDDNQIVTS SGDTTCALWD IETGQQTTTF TGHTGDVMSL SLAPDTRLFV SGACDASAKL WDVREGMCRQ TF TGHESDI NAICFFPNGN AFATGSDDAT CRLFDLRADQ ELMTYSHDNI ICGITSVSFS KSGRLLLAGY DDFNCNVWDA LKA DRAGVL AGHDNRVSCL GVTDDGMAVA TGSWDSFLKI WN

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Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2

MacromoleculeName: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 6.375332 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString:
NTASIAQARK LVEQLKMEAN IDRIKVSKAA ADLMAYCEAH AKEDPLLTPV PASENPFR

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Macromolecule #4: Nb35

MacromoleculeName: Nb35 / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Camelus bactrianus (Bactrian camel)
Molecular weightTheoretical: 13.885439 KDa
Recombinant expressionOrganism: Escherichia coli (E. coli)
SequenceString:
QVQLQESGGG LVQPGGSLRL SCAASGFTFS NYKMNWVRQA PGKGLEWVSD ISQSGASISY TGSVKGRFTI SRDNAKNTLY LQMNSLKPE DTAVYYCARC PAPFTRDCFD VTSTTYAYRG QGTQVTVSS

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Macromolecule #5: 5-hydroxytryptamine receptor 6

MacromoleculeName: 5-hydroxytryptamine receptor 6 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 46.99209 KDa
Recombinant expressionOrganism: Baculovirus expression vector pFastBac1-HM
SequenceString: MVPEPGPTAN STPAWGAGPP SAPGGSGWVA AALCVVIALT AAANSLLIAL ICTQPALRNT SNFFLVSLFT SDLMVGLVVM PPAMLNALY GRWVLARGLC LLWTAFDVMC CSASILNLCL ISLDRYLLIL SPLRYKLRMT PLRALALVLG AWSLAALASF L PLLLGWHE ...String:
MVPEPGPTAN STPAWGAGPP SAPGGSGWVA AALCVVIALT AAANSLLIAL ICTQPALRNT SNFFLVSLFT SDLMVGLVVM PPAMLNALY GRWVLARGLC LLWTAFDVMC CSASILNLCL ISLDRYLLIL SPLRYKLRMT PLRALALVLG AWSLAALASF L PLLLGWHE LGHARPPVPG QCRLLASLPF VLVASGLTFF LPSGAICFTY CRILLAARKQ AVQVASLTTG MASQASETLQ VP RTPRPGV ESADSRRLAT KHSRKALKAS LTLGILLGMF FVTWLPFFVA NIVQAVCDCI SPGLFDVLTW LGYCNSTMNP IIY PLFMRD FKRALGRFLP CPRCPRERQA SLASPSLRTS HSGPRPGLSL QQVLPLPLPP DSDSDSDAGS GGSSGLRLTA QLLL PGEAT QDPPLPTRAA AAVNFFNIDP AEPELRPHPL GIPTN

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Macromolecule #6: 2-(5-chloranyl-2-methyl-1~{H}-indol-3-yl)-N,N-dimethyl-ethanamine

MacromoleculeName: 2-(5-chloranyl-2-methyl-1~{H}-indol-3-yl)-N,N-dimethyl-ethanamine
type: ligand / ID: 6 / Number of copies: 1 / Formula: UQL
Molecular weightTheoretical: 236.74 Da
Chemical component information

ChemComp-UQL:
2-(5-chloranyl-2-methyl-1~{H}-indol-3-yl)-N,N-dimethyl-ethanamine

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

BufferpH: 7.4
VitrificationCryogen name: ETHANE

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Electron microscopy

MicroscopeFEI TITAN KRIOS
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELDBright-field microscopy / Nominal defocus max: 2.5 µm / Nominal defocus min: 1.0 µm
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 60.0 e/Å2
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:

7xtb

Initial angle assignmentType: ANGULAR RECONSTITUTION
Final angle assignmentType: ANGULAR RECONSTITUTION
Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.09 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 286776

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