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- EMDB-29571: 4-F, 5-MeO-PyrT-bound serotonin 1A (5-HT1A) receptor-Gi1 protein ... -
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Open data
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Basic information
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Title | 4-F, 5-MeO-PyrT-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||
![]() | 4-F, 5-MeO-PyrT-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||
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![]() | GPCR Signaling Complex / ![]() ![]() | ||||||||||||||||||
Function / homology | ![]() regulation of serotonin secretion / adenylate cyclase-inhibiting serotonin receptor signaling pathway / regulation of hormone secretion / dopamine neurotransmitter receptor activity, coupled via Gs / ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() ![]() Similarity search - Function | ||||||||||||||||||
Biological species | Escherichia coli, Homo sapiens / ![]() ![]() | ||||||||||||||||||
Method | ![]() ![]() | ||||||||||||||||||
![]() | 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 | ![]() | 31.2 MB | ![]() | |
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Header (meta data) | ![]() ![]() | 24.3 KB 24.3 KB | Display Display | ![]() |
Images | ![]() | 37.3 KB | ||
Filedesc metadata | ![]() | 7.8 KB | ||
Others | ![]() ![]() | 59.4 MB 59.4 MB | ||
Archive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 8fyeMC ![]() 8fy8C ![]() 8fylC ![]() 8fytC ![]() 8fyxC 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 | 4-F, 5-MeO-PyrT-bound serotonin 1A (5-HT1A) receptor-Gi1 protein complex | ||||||||||||||||||||
Voxel size | X=Y=Z: 1.076 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_29571_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_29571_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: 40.415031 KDa |
Recombinant expression | Organism: ![]() ![]() ![]() |
Sequence | String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI ...String: MGCTLSAEDK AAVERSKMID RNLREDGEKA AREVKLLLLG AGESGKSTIV KQMKIIHEAG YSEEECKQYK AVVYSNTIQS IIAIIRAMG RLKIDFGDSA RADDARQLFV LAGAAEEGFM TAELAGVIKR LWKDSGVQAC FNRSREYQLN DSAAYYLNDL D RIAQPNYI PTQQDVLRTR VKTTGIVETH FTFKDLHFKM FDVGGQRSER KKWIHCFEGV TAIIFCVALS DYDLVLAEDE EM NRMHESM KLFDSICNNK WFTDTSIILF LNKKDLFEEK IKKSPLTICY PEYAGSNTYE EAAAYIQCQF EDLNKRKDTK EIY THFTCA 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 in 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 in 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: 4-fluoro-5-methoxy-3-[2-(pyrrolidin-1-yl)ethyl]-1H-indole
Macromolecule | Name: 4-fluoro-5-methoxy-3-[2-(pyrrolidin-1-yl)ethyl]-1H-indole type: ligand / ID: 5 / Number of copies: 1 / Formula: YGH |
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Molecular weight | Theoretical: 262.323 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 | ![]() |
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Aggregation state | particle |
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Sample preparation
Concentration | 18 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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Electron beam | Acceleration voltage: 300 kV / Electron source: ![]() |
Electron optics | Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD![]() |
Image recording | Film or detector model: GATAN K3 (6k x 4k) / Average electron dose: 52.23 e/Å2 |
Experimental equipment | ![]() Model: Titan Krios / Image courtesy: FEI Company |
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Image processing
Particle selection | Number selected: 4565297 |
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Startup model | Type of model: NONE |
Initial angle assignment | Type: MAXIMUM LIKELIHOOD |
Final 3D classification | Software - Name: cryoSPARC |
Final angle assignment | Type: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC |
Final reconstruction | Number classes used: 1 / Resolution.type: BY AUTHOR / Resolution: 2.85 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC Details: NU Refinement performed in cryoSPARC. Reported resolution is from refinement with a tight mask. No mask refinement resolution was 3.3A. Number images used: 265975 |