Cryo-EM Structures of the Human 5-HT_2BR Bound to Three Distinct Ligands Reveal Molecular Determinants of Subtype Selectivity.

Authors

Guangyu Yang, Yixuan Zhong, Haizhan Jiao, Yuyong Tao, Qiong Guo

Published in

FASEB journal : official publication of the Federation of American Societies for Experimental Biology. Volume 40. Issue 12. Pages e71994. Jun 30, 2026.

Abstract

The 5-HT_2BR, a member of the G protein-coupled receptor (GPCR) family, has been implicated in various diseases, including cardiovascular conditions, fibrotic disorders, cancer, and neuropsychiatric illnesses. Despite its therapeutic potential, the 5-HT_2BR remains largely underexplored due to the limited availability of subtype-selective ligands. Additionally, many drugs either exhibit off-target binding to 5-HT_2BR or fail to achieve specificity for their intended receptor subtype. Here, we present three cryo-electron microscopy structures of the human 5-HT_2BR in complex with the antagonist tegaserod, the inverse agonist ritanserin, and the selective antagonist RS127445, respectively. These structures reveal distinct binding modes for each ligand, and through detailed analysis, we identify residues L362 and V366 as key contributors to 5-HT₂ subtype selectivity, while E363 and the ECL2 region play critical roles in 5-HT_2BR subtype selectivity. Our findings offer valuable insights into the molecular mechanisms behind ligand selectivity for 5-HT_2BR, laying the groundwork for the development of 5-HT_2BR-selective ligands.

PMID:
42313494
Bibliographic data and abstract were imported from PubMed on 19 Jun 2026.

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