21ah

LY334370-bound serotonin 1F (5-HT1F) receptor

Structural highlights

21ah is a 1 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 3.18Å
Ligands:	A1E2G
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

5HT1F_HUMAN G-protein coupled receptor for 5-hydroxytryptamine (serotonin) (PubMed:21422162, PubMed:34239069, PubMed:8380639, PubMed:8384716). Also functions as a receptor for various alkaloids and psychoactive substances (PubMed:21422162, PubMed:8380639, PubMed:8384716). Receptor for lasmiditan, a drug for the treatment of acute migraine (PubMed:34239069). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase (PubMed:34239069). HTR1F is coupled to G(i)/G(o) G alpha proteins and mediates inhibitory neurotransmission by inhibiting adenylate cyclase activity (PubMed:34239069, PubMed:35610220).^[1] ^[2] ^[3] ^[4] ^[5]

Publication Abstract from PubMed

The 5-HT(1F) 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-HT(1F)R agonist and demonstrated efficacy in clinical studies. However, the molecular mechanism underlying 5-HT(1F)R activation by LY334370 remains poorly understood. Here, we determined a 3.13 A cryo-EM structure of the LY334370-bound 5-HT(1F)R-miniGalpha(oA) complex. Combined with functional analyses, this structure delineates the molecular determinants underlying LY334370 recognition. Comparison with BRL54443 indicates that LY334370 selectivity for 5-HT(1F)R is driven by its optimal accommodation within the receptor-specific extended binding pocket. Furthermore, comparative analysis with the lasmiditan-bound 5-HT(1F)R-Galpha(i1) complex reveals distinct agonist binding modes and provides mechanistic insight into Galpha(i/o) subtype-specific coupling. Collectively, these findings elucidate the structural basis of 5-HT(1F)R activation, ligand selectivity, and G protein coupling, providing a structural framework for the rational design of safer and more effective anti-migraine drugs.

Structural basis of LY334370 recognition and selectivity at the 5-HT(1F) receptor.,Wang Y, Wang C, Cao C Biochem Biophys Res Commun. 2026 Mar 12;804:153313. doi: , 10.1016/j.bbrc.2026.153313. Epub 2026 Jan 21. PMID:41619505^[6]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Klein MT, Dukat M, Glennon RA, Teitler M. Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships. J Pharmacol Exp Ther. 2011 Jun;337(3):860-7. PMID:21422162 doi:10.1124/jpet.111.179606
↑ Huang S, Xu P, Tan Y, You C, Zhang Y, Jiang Y, Xu HE. Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT(1F)-G protein complex. Cell Res. 2021 Sep;31(9):1036-1038. PMID:34239069 doi:10.1038/s41422-021-00527-4
↑ Tan Y, Xu P, Huang S, Yang G, Zhou F, He X, Ma H, Xu HE, Jiang Y. Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A). Cell Discov. 2022 May 24;8(1):50. PMID:35610220 doi:10.1038/s41421-022-00412-3
↑ Adham N, Kao HT, Schecter LE, Bard J, Olsen M, Urquhart D, Durkin M, Hartig PR, Weinshank RL, Branchek TA. Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):408-12. PMID:8380639 doi:10.1073/pnas.90.2.408
↑ Lovenberg TW, Erlander MG, Baron BM, Racke M, Slone AL, Siegel BW, Craft CM, Burns JE, Danielson PE, Sutcliffe JG. Molecular cloning and functional expression of 5-HT1E-like rat and human 5-hydroxytryptamine receptor genes. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2184-8. PMID:8384716 doi:10.1073/pnas.90.6.2184
↑ Wang Y, Wang C, Cao C. Structural basis of LY334370 recognition and selectivity at the 5-HT(1F) receptor. Biochem Biophys Res Commun. 2026 Mar 12;804:153313. PMID:41619505 doi:10.1016/j.bbrc.2026.153313

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Klein MT, Dukat M, Glennon RA, Teitler M. Toward selective drug development for the human 5-hydroxytryptamine 1E receptor: a comparison of 5-hydroxytryptamine 1E and 1F receptor structure-affinity relationships. J Pharmacol Exp Ther. 2011 Jun;337(3):860-7. PMID:21422162 doi:10.1124/jpet.111.179606

[2] Huang S, Xu P, Tan Y, You C, Zhang Y, Jiang Y, Xu HE. Structural basis for recognition of anti-migraine drug lasmiditan by the serotonin receptor 5-HT(1F)-G protein complex. Cell Res. 2021 Sep;31(9):1036-1038. PMID:34239069 doi:10.1038/s41422-021-00527-4

[3] Tan Y, Xu P, Huang S, Yang G, Zhou F, He X, Ma H, Xu HE, Jiang Y. Structural insights into the ligand binding and G(i) coupling of serotonin receptor 5-HT(5A). Cell Discov. 2022 May 24;8(1):50. PMID:35610220 doi:10.1038/s41421-022-00412-3

[4] Adham N, Kao HT, Schecter LE, Bard J, Olsen M, Urquhart D, Durkin M, Hartig PR, Weinshank RL, Branchek TA. Cloning of another human serotonin receptor (5-HT1F): a fifth 5-HT1 receptor subtype coupled to the inhibition of adenylate cyclase. Proc Natl Acad Sci U S A. 1993 Jan 15;90(2):408-12. PMID:8380639 doi:10.1073/pnas.90.2.408

[5] Lovenberg TW, Erlander MG, Baron BM, Racke M, Slone AL, Siegel BW, Craft CM, Burns JE, Danielson PE, Sutcliffe JG. Molecular cloning and functional expression of 5-HT1E-like rat and human 5-hydroxytryptamine receptor genes. Proc Natl Acad Sci U S A. 1993 Mar 15;90(6):2184-8. PMID:8384716 doi:10.1073/pnas.90.6.2184

[6] Wang Y, Wang C, Cao C. Structural basis of LY334370 recognition and selectivity at the 5-HT(1F) receptor. Biochem Biophys Res Commun. 2026 Mar 12;804:153313. PMID:41619505 doi:10.1016/j.bbrc.2026.153313

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21ah

LY334370-bound serotonin 1F (5-HT1F) receptor

Structural highlights

Function

Publication Abstract from PubMed

References

Contents

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