8FSB

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

Summary for 8FSB

• Entry DOI: 10.2210/pdb8fsb/pdb
• EMDB information: 29409 29410 29411 29418
• Descriptor: 5-hydroxytryptamine receptor 3A, 2-acetamido-2-deoxy-beta-D-glucopyranose, SEROTONIN (3 entities in total)
• Functional Keywords: agonist, cys-loop, plgic, ion channel, transport protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 5
• Total formula weight: 315948.26

Authors

Felt, K.C.,Chakrapani, S. (deposition date: 2023-01-09, release date: 2023-12-27, Last modification date: 2024-05-01)

Primary citation

Felt, 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

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

Experimental method

ELECTRON MICROSCOPY (2.75 Å)