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- EMDB-67446: LY334370-bound serotonin 1F (5-HT1F) receptor-miniGoA protein complex -

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Basic information

Entry
Database: EMDB / ID: EMD-67446
TitleLY334370-bound serotonin 1F (5-HT1F) receptor-miniGoA protein complex
Map data
Sample
  • Complex: GPCR bound with a ligand
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(o) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: 5-hydroxytryptamine receptor 1F
    • Protein or peptide: scFv16
  • Ligand: 4-fluoranyl-~{N}-[3-(1-methylpiperidin-4-yl)-1~{H}-indol-5-yl]benzamide
KeywordsMEMBRANE PROTEIN/IMMUNE SYSTEM / MEMBRANE PROTEIN-IMMUNE SYSTEM complex
Function / homology
Function and homology information


Gi/o-coupled serotonin receptor activity / serotonin receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / mu-type opioid receptor binding / vesicle docking involved in exocytosis / corticotropin-releasing hormone receptor 1 binding / serotonin binding / G protein-coupled dopamine receptor signaling pathway ...Gi/o-coupled serotonin receptor activity / serotonin receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / mu-type opioid receptor binding / vesicle docking involved in exocytosis / corticotropin-releasing hormone receptor 1 binding / serotonin binding / G protein-coupled dopamine receptor signaling pathway / regulation of heart contraction / parallel fiber to Purkinje cell synapse / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / postsynaptic modulation of chemical synaptic transmission / adenylate cyclase-inhibiting serotonin receptor signaling pathway / G protein-coupled serotonin receptor binding / muscle contraction / locomotory behavior / negative regulation of insulin secretion / GABA-ergic synapse / adenylate cyclase-modulating G protein-coupled receptor signaling pathway / G-protein beta/gamma-subunit complex binding / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / Olfactory Signaling Pathway / Activation of the phototransduction cascade / G protein-coupled acetylcholine receptor signaling pathway / G beta:gamma signalling through PLC beta / Presynaptic function of Kainate receptors / Thromboxane signalling through TP receptor / Activation of G protein gated Potassium channels / Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits / G-protein activation / Glucagon signaling in metabolic regulation / G beta:gamma signalling through CDC42 / Prostacyclin signalling through prostacyclin receptor / G beta:gamma signalling through BTK / Synthesis, secretion, and inactivation of Glucagon-like Peptide-1 (GLP-1) / photoreceptor disc membrane / ADP signalling through P2Y purinoceptor 12 / Sensory perception of sweet, bitter, and umami (glutamate) taste / Glucagon-type ligand receptors / Adrenaline,noradrenaline inhibits insulin secretion / Vasopressin regulates renal water homeostasis via Aquaporins / Glucagon-like Peptide-1 (GLP1) regulates insulin secretion / G alpha (z) signalling events / cellular response to catecholamine stimulus / ADP signalling through P2Y purinoceptor 1 / ADORA2B mediated anti-inflammatory cytokines production / 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 / GPER1 signaling / cellular response to prostaglandin E stimulus / heterotrimeric G-protein complex / G-protein beta-subunit binding / G alpha (12/13) signalling events / Inactivation, recovery and regulation of the phototransduction cascade / extracellular vesicle / sensory perception of taste / Thrombin signalling through proteinase activated receptors (PARs) / signaling receptor complex adaptor activity / retina development in camera-type eye / GTPase binding / cell body / G protein activity / fibroblast proliferation / presynaptic membrane / Ca2+ pathway / High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells / G alpha (i) signalling events / G alpha (s) signalling events / phospholipase C-activating G protein-coupled receptor signaling pathway / G alpha (q) signalling events / chemical synaptic transmission / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / Ras protein signal transduction / postsynaptic membrane / cell population proliferation / Extra-nuclear estrogen signaling / G protein-coupled receptor signaling pathway / lysosomal membrane / GTPase activity / synapse / dendrite / GTP binding / protein-containing complex binding / glutamatergic synapse / signal transduction / extracellular exosome / membrane / metal ion binding / plasma membrane / cytoplasm / cytosol
Similarity search - Function
5-Hydroxytryptamine 1F receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / G-protein, gamma subunit ...5-Hydroxytryptamine 1F receptor / 5-hydroxytryptamine receptor family / G-protein alpha subunit, group I / Serpentine type 7TM GPCR chemoreceptor Srsx / G protein alpha subunit, helical insertion / G protein alpha subunit / Guanine nucleotide binding protein (G-protein), alpha subunit / G-protein alpha subunit / G-alpha domain profile. / 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 / G protein beta WD-40 repeat protein / Guanine nucleotide-binding protein, beta subunit / G-protein, beta subunit / G-protein coupled receptors family 1 signature. / 7 transmembrane receptor (rhodopsin family) / G protein-coupled receptor, rhodopsin-like / GPCR, rhodopsin-like, 7TM / G-protein coupled receptors family 1 profile. / 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. / 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(o) subunit alpha / 5-hydroxytryptamine receptor 1F / 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) / Mus musculus (house mouse)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.13 Å
AuthorsCao C / Ji Z / Wang Y
Funding support China, 1 items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)GG910007022 China
CitationJournal: Biochem Biophys Res Commun / Year: 2026
Title: Structural basis of LY334370 recognition and selectivity at the 5-HT receptor.
Authors: Yumeng Wang / Chunyu Wang / Can Cao /
Abstract: The 5-HT receptor is a serotonin receptor subtype highly expressed in trigeminal sensory neurons, where it modulates neuropeptide release and nociceptive signaling without inducing vasoconstriction. ...The 5-HT receptor is a serotonin receptor subtype highly expressed in trigeminal sensory neurons, where it modulates neuropeptide release and nociceptive signaling without inducing vasoconstriction. This makes it an important therapeutic target for migraine. LY334370 was developed as a first-generation selective 5-HTR agonist and demonstrated efficacy in clinical studies. However, the molecular mechanism underlying 5-HTR activation by LY334370 remains poorly understood. Here, we determined a 3.13 Å cryo-EM structure of the LY334370-bound 5-HTR-miniGα complex. Combined with functional analyses, this structure delineates the molecular determinants underlying LY334370 recognition. Comparison with BRL54443 indicates that LY334370 selectivity for 5-HTR is driven by its optimal accommodation within the receptor-specific extended binding pocket. Furthermore, comparative analysis with the lasmiditan-bound 5-HTR-Gα complex reveals distinct agonist binding modes and provides mechanistic insight into Gα subtype-specific coupling. Collectively, these findings elucidate the structural basis of 5-HTR activation, ligand selectivity, and G protein coupling, providing a structural framework for the rational design of safer and more effective anti-migraine drugs.
History
DepositionDec 4, 2025-
Header (metadata) releaseApr 8, 2026-
Map releaseApr 8, 2026-
UpdateApr 8, 2026-
Current statusApr 8, 2026Processing site: PDBc / Status: Released

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Structure visualization

Supplemental images

emd_67446.png

Downloads & links

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Map

FileDownload / File: emd_67446.map.gz / Format: CCP4 / Size: 166.4 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.)
0.82 Å/pix.
x 352 pix.
= 288.64 Å		0.82 Å/pix.
x 352 pix.
= 288.64 Å		0.82 Å/pix.
x 352 pix.
= 288.64 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 0.82 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.08
Minimum - Maximum-0.48536637 - 0.6704539
Average (Standard dev.)-0.00009119348 (±0.009854047)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions352352352
Spacing352352352
CellA=B=C: 288.63998 Å
α=β=γ: 90.0 °

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Supplemental data

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Half map: #2

Fileemd_67446_half_map_1.map
Projections & Slices
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Density Histograms

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Histogram (log scale)

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Half map: #1

Fileemd_67446_half_map_2.map
Projections & Slices
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Histogram (log scale)

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Sample components

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Entire : GPCR bound with a ligand

EntireName: GPCR bound with a ligand
Components
  • Complex: GPCR bound with a ligand
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(T) subunit beta-1
    • Protein or peptide: Guanine nucleotide-binding protein G(o) subunit alpha
    • Protein or peptide: Guanine nucleotide-binding protein G(I)/G(S)/G(O) subunit gamma-2
    • Protein or peptide: 5-hydroxytryptamine receptor 1F
    • Protein or peptide: scFv16
  • Ligand: 4-fluoranyl-~{N}-[3-(1-methylpiperidin-4-yl)-1~{H}-indol-5-yl]benzamide

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Supramolecule #1: GPCR bound with a ligand

SupramoleculeName: GPCR bound with a ligand / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#5
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 138.68 KDa

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Macromolecule #1: 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: 1 / 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 #2: Guanine nucleotide-binding protein G(o) subunit alpha

MacromoleculeName: Guanine nucleotide-binding protein G(o) subunit alpha / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
EC number: Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 25.435102 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: GSMTLSAEDK AAVERSKMIE KNLKEDGISA AKDVKLLLLG ADNSGKSTIV KQMKIIHGGS GGSGGTTGIV ETHFTFKNLH FRLFDVGGQ RSERKKWIHC FEDVTAIIFC VDLSDYNRMH ESLMLFDSIC NNKFFIDTSI ILFLNKKDLF GEKIKKSPLT I CFPEYTGP ...String:
GSMTLSAEDK AAVERSKMIE KNLKEDGISA AKDVKLLLLG ADNSGKSTIV KQMKIIHGGS GGSGGTTGIV ETHFTFKNLH FRLFDVGGQ RSERKKWIHC FEDVTAIIFC VDLSDYNRMH ESLMLFDSIC NNKFFIDTSI ILFLNKKDLF GEKIKKSPLT I CFPEYTGP NTYEDAAAYI QAQFESKNRS PNKEIYCHMT CATDTNNAQV IFDAVTDIII ANNLRGCGLY

UniProtKB: Guanine nucleotide-binding protein G(o) subunit alpha, Guanine nucleotide-binding protein G(o) subunit alpha

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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: 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 #4: 5-hydroxytryptamine receptor 1F

MacromoleculeName: 5-hydroxytryptamine receptor 1F / type: protein_or_peptide / ID: 4 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 41.76198 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MDFLNSSDQN LTSEELLNRM PSKILVSLTL SGLALMTTTI NSLVIAAIIV TRKLHHPANY LICSLAVTDF LVAVLVMPFS IVYIVRESW IMGQVVCDIW LSVDITCCTC SILHLSAIAL DRYRAITDAV EYARKRTPKH AGIMITIVWI ISVFISMPPL F WRHQGTSR ...String:
MDFLNSSDQN LTSEELLNRM PSKILVSLTL SGLALMTTTI NSLVIAAIIV TRKLHHPANY LICSLAVTDF LVAVLVMPFS IVYIVRESW IMGQVVCDIW LSVDITCCTC SILHLSAIAL DRYRAITDAV EYARKRTPKH AGIMITIVWI ISVFISMPPL F WRHQGTSR DDECIIKHDH IVSTIYSTFG AFYIPLALIL ILYYKIYRAA KTLYHKRQAS RIAKEEVNGQ VLLESGEKST KS VSTSYVL EKSLSDPSTD FDKIHSTVRS LRSEFKHEKS WRRQKISGTR ERKAATTLGL ILGAFVICWL PFFVKELVVN VCD KCKISE EMSNFLAWLG YLNSLINPLI YTIFNEDFKK AFQKLVRCRC

UniProtKB: 5-hydroxytryptamine receptor 1F

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Macromolecule #5: scFv16

MacromoleculeName: scFv16 / type: protein_or_peptide / ID: 5 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Mus musculus (house mouse)
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: 4-fluoranyl-~{N}-[3-(1-methylpiperidin-4-yl)-1~{H}-indol-5-yl]ben...

MacromoleculeName: 4-fluoranyl-~{N}-[3-(1-methylpiperidin-4-yl)-1~{H}-indol-5-yl]benzamide
type: ligand / ID: 6 / Number of copies: 1 / Formula: A1E2G
Molecular weightTheoretical: 351.417 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

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Electron microscopy

MicroscopeTFS KRIOS
Image recordingFilm or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Average electron dose: 50.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.8 µm
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionType: NONE
Startup modelType of model: PDB ENTRY
PDB model - PDB ID:

7exd

Final reconstructionResolution.type: BY AUTHOR / Resolution: 3.13 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.4.1) / Number images used: 114556
Initial angle assignmentType: MAXIMUM LIKELIHOOD
Final angle assignmentType: MAXIMUM LIKELIHOOD
FSC plot (resolution estimation)

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