8FRX

Full-length mouse 5-HT3A receptor in complex with SMP100, pre-activated

8FRX の概要

• エントリーDOI: 10.2210/pdb8frx/pdb
• EMDBエントリー: 29409 29410 29411 29418 29421
• 分子名称: 5-hydroxytryptamine receptor 3A, 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, 2-acetamido-2-deoxy-beta-D-glucopyranose (3 entities in total)
• 機能のキーワード: partial agonist, cys-loop, plgic, ion channel, transport protein
• 由来する生物種: Mus musculus (house mouse)
• タンパク質・核酸の鎖数: 5
• 化学式量合計: 316549.02

構造登録者

Felt, K.C.,Chakrapani, S. (登録日: 2023-01-09, 公開日: 2023-12-27, 最終更新日: 2024-11-13)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (2.7 Å)