High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition

• DOI: 10.7554/elife.57870
• Publication Date: 2020-10-16T12:00:38Z
• Authors: Sandip Basak; Arvind Kumar; Steven Ramsey; Eric Gibbs; Abhijeet Kapoor; Marta Filizola; Sudha Chakrapani
• Keywords: Serotonin; QH301-705.5; Protein Conformation; Science; Molecular Dynamics Simulation; Ligands; Binding, Competitive; Mice; Xenopus laevis; 03 medical and health sciences; Biochemistry and Chemical Biology; anti-emetic; Animals; Humans; Biology (General); 0303 health sciences; Binding Sites; Q; Cryoelectron Microscopy; Setron; R; ion channels; 3. Good health; Oocytes; Medicine; Female; Serotonin Antagonists; Receptors, Serotonin, 5-HT3; Protein Binding

Serotonin receptors (5-HT3AR) play a crucial role in regulating gut movement, and are the principal target of setrons, a class of high-affinity competitive antagonists, used in the management of nausea and vomiting associated with radiation and chemotherapies. Structural insights into setron-binding poses and their inhibitory mechanisms are just beginning to emerge. Here, we present high-resolution cryo-EM structures of full-length 5-HT3AR in complex with palonosetron, ondansetron, and alosetron. Molecular dynamic simulations of these structures embedded in a fully-hydrated lipid environment assessed the stability of ligand-binding poses and drug-target interactions over time. Together with simulation results of apo- and serotonin-bound 5-HT3AR, the study reveals a distinct interaction fingerprint between the various setrons and binding-pocket residues that may underlie their diverse affinities. In addition, varying degrees of conformational change in the setron-5-HT3AR structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.