Molecular mechanism of setron-mediated inhibition of full-length 5-HT3A receptor

• DOI: 10.1038/s41467-019-11142-8
• Publication Date: 2019-07-19T10:03:00Z
• Authors: Sandip Basak; Yvonne Gicheru; Abhijeet Kapoor; Megan L. Mayer; Marta Filizola; Sudha Chakrapani
• Keywords: Granisetron; Serotonin Antagonists

Abstract Serotonin receptor (5-HT 3A R) is the most common therapeutic target to manage nausea and vomiting during cancer therapies in treatment of irritable bowel syndrome. Setrons, a class competitive antagonists, cause functional inhibition 5-HT R gastrointestinal tract brainstem, acting as effective anti-emetic agents. Despite their prevalent use, molecular mechanisms underlying setron binding are not fully understood. Here, we present structure granisetron-bound full-length solved by single-particle cryo-electron microscopy 2.92 Å resolution. The reconstruction reveals orientation granisetron orthosteric site with unambiguous density for interacting sidechains. Molecular dynamics simulations electrophysiology confirm residues central ligand recognition. Comparison apo serotonin-bound structures, key insights into mechanism inhibition.