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- EMDB-29599: Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex -
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Open data
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Basic information
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Title | Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||
![]() | Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||
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![]() | GPCR Signaling Complex / Serotonin Receptor / SIGNALING PROTEIN | ||||||||||||||||||
Function / homology | ![]() regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / Serotonin receptors / receptor-receptor interaction / serotonin receptor signaling pathway / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding ...regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / regulation of behavior / Serotonin receptors / receptor-receptor interaction / serotonin receptor signaling pathway / regulation of dopamine metabolic process / serotonin metabolic process / serotonin binding / G protein-coupled serotonin receptor activity / gamma-aminobutyric acid signaling pathway / exploration behavior / neurotransmitter receptor activity / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / regulation of vasoconstriction / Adenylate cyclase inhibitory pathway / behavioral fear response / positive regulation of protein localization to cell cortex / regulation of cAMP-mediated signaling / D2 dopamine receptor binding / G protein-coupled serotonin receptor binding / regulation of mitotic spindle organization / cellular response to forskolin / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Regulation of insulin secretion / G protein-coupled receptor binding / G-protein beta/gamma-subunit complex binding / Olfactory Signaling Pathway / Activation of the phototransduction cascade / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / G protein-coupled acetylcholine receptor signaling pathway / G-protein activation / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / Prostacyclin signalling through prostacyclin receptor / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / response to peptide hormone / 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 / Glucagon-type ligand receptors / Vasopressin regulates renal water homeostasis via Aquaporins / G alpha (z) signalling events / cellular response to catecholamine stimulus / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / sensory perception of taste / ADP signalling through P2Y purinoceptor 1 / adenylate cyclase-activating dopamine receptor signaling pathway / G beta:gamma signalling through PI3Kgamma / cellular response to prostaglandin E stimulus / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / GPER1 signaling / GDP binding / 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 / Thrombin signalling through proteinase activated receptors (PARs) / GTPase binding / retina development in camera-type eye / Ca2+ pathway / phospholipase C-activating G protein-coupled receptor signaling pathway / cell cortex / midbody / G alpha (i) signalling events / fibroblast proliferation / G alpha (s) signalling events / G alpha (q) signalling events / chemical synaptic transmission / Ras protein signal transduction / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / cell division / lysosomal membrane / GTPase activity / centrosome / synapse / dendrite / positive regulation of cell population proliferation / protein-containing complex binding / nucleolus / GTP binding / magnesium ion binding / signal transduction / extracellular exosome / nucleoplasm / membrane / plasma membrane Similarity search - Function | ||||||||||||||||||
Biological species | Escherichia coli, Homo sapiens / ![]() | ||||||||||||||||||
Method | single particle reconstruction / cryo EM / Resolution: 2.62 Å | ||||||||||||||||||
![]() | Warren AL / Zilberg G / Capper MJ / Wacker D | ||||||||||||||||||
Funding support | ![]()
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![]() | ![]() Title: Structural pharmacology and therapeutic potential of 5-methoxytryptamines. Authors: Audrey L Warren / David Lankri / Michael J Cunningham / Inis C Serrano / Lyonna F Parise / Andrew C Kruegel / Priscilla Duggan / Gregory Zilberg / Michael J Capper / Vaclav Havel / Scott J ...Authors: Audrey L Warren / David Lankri / Michael J Cunningham / Inis C Serrano / Lyonna F Parise / Andrew C Kruegel / Priscilla Duggan / Gregory Zilberg / Michael J Capper / Vaclav Havel / Scott J Russo / Dalibor Sames / Daniel Wacker / ![]() Abstract: Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their ...Psychedelic substances such as lysergic acid diethylamide (LSD) and psilocybin show potential for the treatment of various neuropsychiatric disorders. These compounds are thought to mediate their hallucinogenic and therapeutic effects through the serotonin (5-hydroxytryptamine (5-HT)) receptor 5-HT (ref. ). However, 5-HT also plays a part in the behavioural effects of tryptamine hallucinogens, particularly 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), a psychedelic found in the toxin of Colorado River toads. Although 5-HT is a validated therapeutic target, little is known about how psychedelics engage 5-HT and which effects are mediated by this receptor. Here we map the molecular underpinnings of 5-MeO-DMT pharmacology through five cryogenic electron microscopy (cryo-EM) structures of 5-HT, systematic medicinal chemistry, receptor mutagenesis and mouse behaviour. Structure-activity relationship analyses of 5-methoxytryptamines at both 5-HT and 5-HT enable the characterization of molecular determinants of 5-HT signalling potency, efficacy and selectivity. Moreover, we contrast the structural interactions and in vitro pharmacology of 5-MeO-DMT and analogues to the pan-serotonergic agonist LSD and clinically used 5-HT agonists. We show that a 5-HT-selective 5-MeO-DMT analogue is devoid of hallucinogenic-like effects while retaining anxiolytic-like and antidepressant-like activity in socially defeated animals. Our studies uncover molecular aspects of 5-HT-targeted psychedelics and therapeutics, which may facilitate the future development of new medications for neuropsychiatric disorders. | ||||||||||||||||||
History |
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Structure visualization
Supplemental images |
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Downloads & links
-EMDB archive
Map data | ![]() | 70.1 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 24.2 KB 24.2 KB | Display Display | ![]() |
FSC (resolution estimation) | ![]() | 11 KB | Display | ![]() |
Images | ![]() | 37.9 KB | ||
Filedesc metadata | ![]() | 7.7 KB | ||
Others | ![]() ![]() | 134.2 MB 134.2 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8fyxMC ![]() 8fy8C ![]() 8fyeC ![]() 8fylC ![]() 8fytC M: atomic model generated by this map C: citing same article ( |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
EMDB pages | ![]() ![]() |
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Related items in Molecule of the Month |
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Map
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Annotation | Buspirone-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||||
Voxel size | X=Y=Z: 0.82 Å | ||||||||||||||||||||
Density |
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Symmetry | Space group: 1 | ||||||||||||||||||||
Details | EMDB XML:
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-Supplemental data
-Half map: Half Map 1
File | emd_29599_half_map_1.map | ||||||||||||
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Annotation | Half Map 1 | ||||||||||||
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Density Histograms |
-Half map: Half Map 2
File | emd_29599_half_map_2.map | ||||||||||||
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Annotation | Half Map 2 | ||||||||||||
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Density Histograms |
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Sample components
-Entire : Serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Entire | Name: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex |
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Components |
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-Supramolecule #1: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex
Supramolecule | Name: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#4 Details: Serotonin 1A (5-HT1A) receptor-Gi1 protein complex with components purified separately and assembled in vitro. |
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Source (natural) | Organism: Escherichia coli, Homo sapiens |
-Macromolecule #1: Guanine nucleotide-binding protein G(i) subunit alpha-1
Macromolecule | Name: Guanine nucleotide-binding protein G(i) subunit alpha-1 type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 40.414047 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKNTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGAQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHASM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCS TDTKNVQFVF DAVTDVIIKN NLKDCGLF UniProtKB: Guanine nucleotide-binding protein G(i) subunit alpha-1 |
-Macromolecule #2: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
Macromolecule | Name: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 type: protein_or_peptide / ID: 2 Details: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 with n-terminal his-tag and 3C cleavage site and GSSG linker Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 39.418086 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: 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 UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1 |
-Macromolecule #3: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
Macromolecule | Name: 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 |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 8.506765 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI LGSAGSAGSA UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2 |
-Macromolecule #4: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A,5-hydroxy...
Macromolecule | Name: Soluble cytochrome b562,5-hydroxytryptamine receptor 1A,5-hydroxytryptamine receptor 1A type: protein_or_peptide / ID: 4 Details: N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point ...Details: N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point mutation at position 255 in the provided sequence. This mutation is Ballesteros-Weinstein position 3.41 of 5-HT1A where the original leucine was mutated to a tryptophan. Cytochrome b562 (cybC, UniProt P0ABE7) is both n and c-terminally truncated with two point mutations.,N-terminal HA signal sequence, flag-tag, his-tag, tev cleavage site followed by soluble cytochrome b562 (E. coli) and truncated 5-hydroxytryptamine receptor 1A (Homo sapiens) with a point mutation at position 255 in the provided sequence. This mutation is Ballesteros-Weinstein position 3.41 of 5-HT1A where the original leucine was mutated to a tryptophan. Cytochrome b562 (cybC, UniProt P0ABE7) is both n and c-terminally truncated with two point mutations. Number of copies: 1 / Enantiomer: LEVO |
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Source (natural) | Organism: ![]() |
Molecular weight | Theoretical: 61.37593 KDa |
Recombinant expression | Organism: ![]() ![]() |
Sequence | String: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTTA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLTGIS D VTVSYQVI ...String: MKTIIALSYI FCLVFADYKD DDDAKLQTMH HHHHHHHHHE NLYFQGGTTA DLEDNWETLN DNLKVIEKAD NAAQVKDALT KMRAAALDA QKATPPKLED KSPDSPEMKD FRHGFDILVG QIDDALKLAN EGKVKEAQAA AEQLKTTRNA YIQKYLTGIS D VTVSYQVI TSLLLGTLIF CAVLGNACVV AAIALERSLQ NVANYLIGSL AVTDLMVSVL VLPMAALYQV LNKWTLGQVT CD LFIALDV LCCTSSIWHL CAIALDRYWA ITDPIDYVNK RTPRRAAALI SLTWLIGFLI SIPPMLGWRT PEDRSDPDAC TIS KDHGYT IYSTFGAFYI PLLLMLVLYG RIFRAARFRI RKTVKKVEKT GADTRHGASP APQPKKSVNG ESGSRNWRLG VESK AGGAL CANGAVRQGD DGAALEVIEV HRVGNSKEHL PLPSEAGPTP CAPASFERKN ERNAEAKRKM ALARERKTVK TLGII MGTF ILCWLPFFIV ALVLPFCESS CHMPTLLGAI INWLGYSNSL LNPVIYAYFN KDFQNAFKKI IKCKFCRQ UniProtKB: 5-hydroxytryptamine receptor 1A |
-Macromolecule #5: Buspirone
Macromolecule | Name: Buspirone / type: ligand / ID: 5 / Number of copies: 1 / Formula: YLX |
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Molecular weight | Theoretical: 385.503 Da |
-Macromolecule #6: [(2R)-1-[oxidanyl-[(2R,3R,5S,6R)-2,3,5,6-tetrakis(oxidanyl)-4-pho...
Macromolecule | Name: [(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 type: ligand / ID: 6 / Number of copies: 1 / Formula: J40 |
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Molecular weight | Theoretical: 854.895 Da |
Chemical component information | ![]() ChemComp-J40: |
-Macromolecule #7: CHOLESTEROL HEMISUCCINATE
Macromolecule | Name: CHOLESTEROL HEMISUCCINATE / type: ligand / ID: 7 / Number of copies: 2 / Formula: Y01 |
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Molecular weight | Theoretical: 486.726 Da |
Chemical component information | ![]() ChemComp-Y01: |
-Experimental details
-Structure determination
Method | cryo EM |
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![]() | single particle reconstruction |
Aggregation state | particle |
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Sample preparation
Concentration | 24 mg/mL | ||||||||||||
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Buffer | pH: 7.4 Component:
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Grid | Model: Quantifoil / Material: COPPER / Mesh: 300 / Support film - Material: CARBON / Support film - topology: HOLEY / Pretreatment - Type: GLOW DISCHARGE | ||||||||||||
Vitrification | Cryogen name: ETHANE / Instrument: LEICA EM GP Details: Blot force 3 for 3-5 seconds was used and subsequent grids were screened for ice thickness prior to data collection.. | ||||||||||||
Details | Sample was mono disperse following gel filtration. The sample was immediately concentrated for CryoEM grid preparation. |
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Electron microscopy
Microscope | FEI TITAN KRIOS |
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Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 50.0 e/Å2 |
Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 2.5 µm / Nominal defocus min: 0.5 µm |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |