21ag

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

spinqualitylabelsall models 21ag, resolution 3.13Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 21ag is a 5 chain structure with sequence from Homo sapiens and Mus musculus. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: Electron Microscopy, Resolution 3.13Å Ligands: A1E2G Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function GBB1_HUMAN Guanine nucleotide-binding proteins (G proteins) are involved as a modulator or transducer in various transmembrane signaling systems. The beta and gamma chains are required for the GTPase activity, for replacement of GDP by GTP, and for G protein-effector interaction. 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 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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