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8FSP

Full-length mouse 5-HT3A receptor in complex with SMP100, open-like

Summary for 8FSP
Entry DOI10.2210/pdb8fsp/pdb
EMDB information29409 29410 29411 29418 29421
Descriptor5-hydroxytryptamine receptor 3A, 2-acetamido-2-deoxy-beta-D-glucopyranose, 5-[(1R,3S,4R)-1-azabicyclo[2.2.2]octan-3-yl]-1,3,4,5-tetrahydro-6H-azepino[5,4,3-cd]indazol-6-one (3 entities in total)
Functional Keywordspartial agonist, cys-loop, plgic, ion channel, transport protein
Biological sourceMus musculus (house mouse)
Total number of polymer chains5
Total formula weight316549.02
Authors
Felt, K.C.,Chakrapani, S. (deposition date: 2023-01-10, release date: 2023-12-27, Last modification date: 2024-10-09)
Primary citationFelt, K.,Stauffer, M.,Salas-Estrada, L.,Guzzo, P.R.,Xie, D.,Huang, J.,Filizola, M.,Chakrapani, S.
Structural basis for partial agonism in 5-HT 3A receptors.
Nat.Struct.Mol.Biol., 31:598-609, 2024
Cited by
PubMed Abstract: Hyperactivity of serotonin 3 receptors (5-HTR) 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-HTR 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-HTR.
PubMed: 38177669
DOI: 10.1038/s41594-023-01140-2
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (3.79 Å)
Structure validation

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