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- PDB-21ah: LY334370-bound serotonin 1F (5-HT1F) receptor -

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Basic information

Entry
Database: PDB / ID: 21ah
TitleLY334370-bound serotonin 1F (5-HT1F) receptor
Components5-hydroxytryptamine receptor 1F
KeywordsMEMBRANE PROTEIN
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 / serotonin binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G alpha (i) signalling events ...Gi/o-coupled serotonin receptor activity / serotonin receptor activity / Serotonin receptors / G protein-coupled serotonin receptor activity / neurotransmitter receptor activity / serotonin binding / G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger / adenylate cyclase-inhibiting serotonin receptor signaling pathway / adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway / G alpha (i) signalling events / chemical synaptic transmission / synapse / dendrite / plasma membrane
Similarity search - Function
5-Hydroxytryptamine 1F receptor / 5-hydroxytryptamine receptor family / Serpentine type 7TM GPCR chemoreceptor Srsx / 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.
Similarity search - Domain/homology
: / 5-hydroxytryptamine receptor 1F
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.18 Å
AuthorsCao, C. / Ji, Z. / Wang, Y.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)GG9100007022 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, 2025Deposition site: PDBJ / Processing site: PDBC
Revision 1.0Apr 8, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: FSC / Data content type: FSC / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
R: 5-hydroxytryptamine receptor 1F
hetero molecules


Theoretical massNumber of molelcules
Total (without water)42,1132
Polymers41,7621
Non-polymers3511
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein 5-hydroxytryptamine receptor 1F / 5-HT-1F / 5-HT1F / Serotonin receptor 1F


Mass: 41761.980 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: HTR1F, HTR1EL / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P30939
#2: Chemical ChemComp-A1E2G / 4-fluoranyl-~{N}-[3-(1-methylpiperidin-4-yl)-1~{H}-indol-5-yl]benzamide


Mass: 351.417 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H22FN3O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: GPCR bound with a ligand / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightValue: 0.04171 MDa / Experimental value: NO
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Spodoptera frugiperda (fall armyworm)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1600 nm / Nominal defocus min: 800 nm
Image recordingElectron dose: 50 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k)

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4.4.1particle selection
12cryoSPARC4.4.13D reconstruction
13PHENIX1.21.2model refinement
CTF correctionType: NONE
3D reconstructionResolution: 3.18 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 114556 / Symmetry type: POINT
RefinementCross valid method: NONE

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