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Full-length mouse 5-HT3A receptor in complex with ALB148471, pre-activated
Structural highlights
Function5HT3A_MOUSE This is one of the several different receptors for 5-hydroxytryptamine (serotonin), a biogenic hormone that functions as a neurotransmitter, a hormone, and a mitogen. This receptor is a ligand-gated ion channel, which when activated causes fast, depolarizing responses in neurons. It is a cation-specific, but otherwise relatively nonselective, ion channel. Publication Abstract from PubMedHyperactivity of serotonin 3 receptors (5-HT(3)R) underlies pathologies associated with irritable bowel syndrome and chemotherapy-induced nausea and vomiting. Setrons, a class of high-affinity competitive antagonists, are used in the treatment of these conditions. Although generally effective for chemotherapy-induced nausea and vomiting, the use of setrons for treating irritable bowel syndrome has been impaired by adverse side effects. Partial agonists are now being considered as an alternative strategy, with potentially less severe side effects than full antagonists. However, a structural understanding of how these ligands work is lacking. Here, we present high-resolution cryogenic electron microscopy structures of the mouse 5-HT(3A)R in complex with partial agonists (SMP-100 and ALB-148471) captured in pre-activated and open-like conformational states. Molecular dynamics simulations were used to assess the stability of drug-binding poses and interactions with the receptor over time. Together, these studies reveal mechanisms for the functional differences between orthosteric partial agonists, full agonists and antagonists of the 5-HT(3A)R. Structural basis for partial agonism in 5-HT(3A) receptors.,Felt K, Stauffer M, Salas-Estrada L, Guzzo PR, Xie D, Huang J, Filizola M, Chakrapani S Nat Struct Mol Biol. 2024 Apr;31(4):598-609. doi: 10.1038/s41594-023-01140-2. , Epub 2024 Jan 4. PMID:38177669[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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