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- EMDB-43800: Global reconstruction of 5-HT2AR bound to 2-bromo-LSD in complex ... -

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Entry
Database: EMDB / ID: EMD-43800
TitleGlobal reconstruction of 5-HT2AR bound to 2-bromo-LSD in complex with a mini-Gq protein and scFv16 obtained by cryo-electron microscopy (cryoEM)
Map data
Sample
  • Complex: 5-HT2AR in complex with mini-Gq
    • Protein or peptide: 5-hydroxytryptamine receptor 2A
  • Protein or peptide: G subunit q (Gi2-mini-Gq chimeric)
  • 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: single chain Fab (svFv16)
  • Ligand: 2-bromo-N,N-diethyl-6-methyl-9,10-didehydroergoline-8beta-carboxamide
KeywordsGPCR / G-protein Coupled Receptor / 5-HT2AR / serotonin / psychedelics / MEMBRANE PROTEIN
Function / homology
Function and homology information


positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / Serotonin receptors / serotonin receptor activity ...positive regulation of heat generation / protein localization to cytoskeleton / 1-(4-iodo-2,5-dimethoxyphenyl)propan-2-amine binding / Gq/11-coupled serotonin receptor activity / positive regulation of phosphatidylinositol biosynthetic process / G protein-coupled serotonin receptor signaling pathway / G protein-coupled serotonin receptor complex / neurofilament / Serotonin receptors / serotonin receptor activity / cell body fiber / phospholipase C-activating serotonin receptor signaling pathway / positive regulation of cytokine production involved in immune response / G protein-coupled serotonin receptor activity / artery smooth muscle contraction / serotonin receptor signaling pathway / sensitization / urinary bladder smooth muscle contraction / serotonin binding / negative regulation of synaptic transmission, glutamatergic / positive regulation of platelet aggregation / positive regulation of DNA biosynthetic process / neurotransmitter receptor activity / temperature homeostasis / regulation of dopamine secretion / negative regulation of potassium ion transport / behavioral response to cocaine / detection of temperature stimulus involved in sensory perception of pain / protein tyrosine kinase activator activity / positive regulation of execution phase of apoptosis / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / positive regulation of fat cell differentiation / detection of mechanical stimulus involved in sensory perception of pain / positive regulation of vasoconstriction / release of sequestered calcium ion into cytosol / presynaptic modulation of chemical synaptic transmission / dendritic shaft / positive regulation of glycolytic process / glycolytic process / caveola / memory / Olfactory Signaling Pathway / Activation of the phototransduction cascade / 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 / intracellular calcium ion homeostasis / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through CDC42 / Glucagon signaling in metabolic regulation / positive regulation of inflammatory response / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / photoreceptor disc membrane / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / positive regulation of peptidyl-tyrosine phosphorylation / G alpha (z) signalling events / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / ADORA2B mediated anti-inflammatory cytokines production / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / G beta:gamma signalling through PI3Kgamma / adenylate cyclase-activating dopamine receptor signaling pathway / Cooperation of PDCL (PhLP1) and TRiC/CCT in G-protein beta folding / positive regulation of neuron apoptotic process / GPER1 signaling / Inactivation, recovery and regulation of the phototransduction cascade / cellular response to prostaglandin E stimulus / G-protein beta-subunit binding / heterotrimeric G-protein complex / G alpha (12/13) signalling events / sensory perception of taste / extracellular vesicle / signaling receptor complex adaptor activity / Thrombin signalling through proteinase activated receptors (PARs) / presynaptic membrane / virus receptor activity / GTPase binding / Ca2+ pathway / retina development in camera-type eye / positive regulation of cytosolic calcium ion concentration / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / fibroblast proliferation / cytoplasmic vesicle / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (i) signalling events / G alpha (s) signalling events / chemical synaptic transmission / G alpha (q) signalling events / postsynaptic membrane / Ras protein signal transduction / positive regulation of ERK1 and ERK2 cascade
Similarity search - Function
5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain ...5-Hydroxytryptamine 2A receptor / 5-hydroxytryptamine receptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / G-protein, gamma subunit / G-protein gamma subunit domain profile. / G-protein gamma-like domain / G-protein gamma-like domain superfamily / GGL domain / G protein gamma subunit-like motifs / GGL domain / 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. / Trp-Asp (WD) repeats profile. / Trp-Asp (WD) repeats circular profile. / WD domain, G-beta repeat / WD40 repeats / WD40 repeat / WD40-repeat-containing domain superfamily / WD40/YVTN repeat-like-containing domain superfamily
Similarity search - Domain/homology
5-hydroxytryptamine receptor 2A / 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
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.38 Å
AuthorsGumpper RH / Fay JF / Roth BL
Funding support United States, 1 items
OrganizationGrant numberCountry
Defense Advanced Research Projects Agency (DARPA)HR0011-20-2-0029 United States
CitationJournal: Nat Commun / Year: 2025
Title: The structural diversity of psychedelic drug actions revealed.
Authors: Ryan H Gumpper / Manish K Jain / Kuglae Kim / Renhong Sun / Ning Sun / Zhongli Xu / Jeffrey F DiBerto / Brian E Krumm / Nicholas J Kapolka / H Ümit Kaniskan / David E Nichols / Jian Jin / ...Authors: Ryan H Gumpper / Manish K Jain / Kuglae Kim / Renhong Sun / Ning Sun / Zhongli Xu / Jeffrey F DiBerto / Brian E Krumm / Nicholas J Kapolka / H Ümit Kaniskan / David E Nichols / Jian Jin / Jonathan F Fay / Bryan L Roth /
Abstract: There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A ...There is currently a resurgence in exploring the utility of classical psychedelics to treat depression, addiction, anxiety disorders, cluster headaches, and many other neuropsychiatric disorders. A biological target of these compounds, and a hypothesized target for their therapeutic actions, is the 5-HT serotonin receptor. Here, we present 7 cryo-EM structures covering all major compound classes of psychedelic and non-psychedelic agonists, including a β-arrestin-biased compound RS130-180. Identifying the molecular interactions between various psychedelics and the 5-HT receptor reveals both common and distinct motifs among the examined psychedelic chemotypes. These findings lead to a broader mechanistic understanding of 5-HT activation, which can catalyze the development of novel chemotypes with potential therapeutic utility and fewer side effects.
History
DepositionFeb 24, 2024-
Header (metadata) releaseApr 2, 2025-
Map releaseApr 2, 2025-
UpdateApr 2, 2025-
Current statusApr 2, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_43800.png

Downloads & links

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Map

FileDownload / File: emd_43800.map.gz / Format: CCP4 / Size: 91.1 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
0.88 Å/pix.
x 288 pix.
= 253.44 Å		0.88 Å/pix.
x 288 pix.
= 253.44 Å		0.88 Å/pix.
x 288 pix.
= 253.44 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.88 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.263
Minimum - Maximum-2.638613 - 3.7738225
Average (Standard dev.)-0.003239894 (±0.06300851)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions288288288
Spacing288288288
CellA=B=C: 253.44 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_43800_msk_1.map
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Half map: #2

Fileemd_43800_half_map_1.map
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Half map: #1

Fileemd_43800_half_map_2.map
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Sample components

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Entire : 5-HT2AR in complex with mini-Gq

EntireName: 5-HT2AR in complex with mini-Gq
Components
  • Complex: 5-HT2AR in complex with mini-Gq
    • Protein or peptide: 5-hydroxytryptamine receptor 2A
  • Protein or peptide: G subunit q (Gi2-mini-Gq chimeric)
  • 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: single chain Fab (svFv16)
  • Ligand: 2-bromo-N,N-diethyl-6-methyl-9,10-didehydroergoline-8beta-carboxamide

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Supramolecule #1: 5-HT2AR in complex with mini-Gq

SupramoleculeName: 5-HT2AR in complex with mini-Gq / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: 5-hydroxytryptamine receptor 2A

MacromoleculeName: 5-hydroxytryptamine receptor 2A / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 52.648945 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDILCEENTS LSSTTNSLMQ LNDDTRLYSN DFNSGEANTS DAFNWTVDSE NRTNLSCEGC LSPSCLSLLH LQEKNWSALL TAVVIILTI AGNILVIMAV SLEKKLQNAT NYFLMSLAIA DMLLGFLVMP VSMLTILYGY RWPLPSKLCA VWIYLDVLFS T ASIMHLCA ...String:
MDILCEENTS LSSTTNSLMQ LNDDTRLYSN DFNSGEANTS DAFNWTVDSE NRTNLSCEGC LSPSCLSLLH LQEKNWSALL TAVVIILTI AGNILVIMAV SLEKKLQNAT NYFLMSLAIA DMLLGFLVMP VSMLTILYGY RWPLPSKLCA VWIYLDVLFS T ASIMHLCA ISLDRYVAIQ NPIHHSRFNS RTKAFLKIIA VWTISVGISM PIPVFGLQDD SKVFKEGSCL LADDNFVLIG SF VSFFIPL TIMVITYFLT IKSLQKEATL CVSDLGTRAK LASFSFLPQS SLSSEKLFQR SIHREPGSYT GRRTMQSISN EQK ACKVLG IVFFLFVVMW CPFFITNIMA VICKESCNED VIGALLNVFV WIGYLSSAVN PLVYTLFNKT YRSAFSRYIQ CQYK ENKKP LQLILVNTIP ALAYKSSQLQ MGQKKNSKQD AKTTDNDCSM VALGKQHSEE ASKDNSDGVN EKVSCV

UniProtKB: 5-hydroxytryptamine receptor 2A

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Macromolecule #2: G subunit q (Gi2-mini-Gq chimeric)

MacromoleculeName: G subunit q (Gi2-mini-Gq chimeric) / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.084832 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA ...String:
MGSTVSAEDK AAAERSKMID KNLREDGEKA RRTLRLLLLG ADNSGKSTIV KQMRILHGGS GGSGGTSGIF ETKFQVDKVN FHMFDVGGQ RDERRKWIQC FNDVTAIIFV VDSSDYNRLQ EALNDFKSIW NNRWLRTISV ILFLNKQDLL AEKVLAGKSK I EDYFPEFA RYTTPEDATP EPGEDPRVTR AKYFIRKEFV DISTASGDGR HICYPHFTCA VDTENARRIF NDCKDIILQM NL REYNLV

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Macromolecule #3: 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: 3 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.418086 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
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

UniProtKB: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1

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Macromolecule #4: 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: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 7.861143 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString:
MASNNTASIA QARKLVEQLK MEANIDRIKV SKAAADLMAY CEAHAKEDPL LTPVPASENP FREKKFFCAI L

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

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Macromolecule #5: single chain Fab (svFv16)

MacromoleculeName: single chain Fab (svFv16) / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 28.668922 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS ...String:
DVQLVESGGG LVQPGGSRKL SCSASGFAFS SFGMHWVRQA PEKGLEWVAY ISSGSGTIYY ADTVKGRFTI SRDDPKNTLF LQMTSLRSE DTAMYYCVRS IYYYGSSPFD FWGQGTTLTV SSGGGGSGGG GSGGGGSDIV MTQATSSVPV TPGESVSISC R SSKSLLHS NGNTYLYWFL QRPGQSPQLL IYRMSNLASG VPDRFSGSGS GTAFTLTISR LEAEDVGVYY CMQHLEYPLT FG AGTKLEL KAAALEVLFQ GPHHHHHHHH

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Macromolecule #6: 2-bromo-N,N-diethyl-6-methyl-9,10-didehydroergoline-8beta-carboxamide

MacromoleculeName: 2-bromo-N,N-diethyl-6-methyl-9,10-didehydroergoline-8beta-carboxamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1AFU
Molecular weightTheoretical: 402.328 Da

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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-PROPANE

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Electron microscopy

MicroscopeFEI TALOS ARCTICA
Image recordingFilm or detector model: GATAN K3 (6k x 4k) / Average electron dose: 49.5 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: OTHER / Imaging mode: OTHER / Nominal defocus max: 2.6 µm / Nominal defocus min: 0.16 µm
Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company

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Image processing

Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7ran

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.38 Å / Resolution method: FSC 0.143 CUT-OFF / Number images used: 603297
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: ANGULAR RECONSTITUTION

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