@article {10.7554/eLife.57870, article_type = {journal}, title = {High-resolution structures of multiple 5-HT\textsubscript{3A}R-setron complexes reveal a novel mechanism of competitive inhibition}, author = {Basak, Sandip and Kumar, Arvind and Ramsey, Steven and Gibbs, Eric and Kapoor, Abhijeet and Filizola, Marta and Chakrapani, Sudha}, editor = {Czajkowski, Cynthia M and Boudker, Olga and Czajkowski, Cynthia M}, volume = 9, year = 2020, month = {oct}, pub_date = {2020-10-16}, pages = {e57870}, citation = {eLife 2020;9:e57870}, doi = {10.7554/eLife.57870}, url = {https://doi.org/10.7554/eLife.57870}, abstract = {Serotonin receptors (5-HT\textsubscript{3A}R) 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-HT\textsubscript{3A}R 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-HT\textsubscript{3A}R, 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-HT\textsubscript{3A}R structures, throughout the channel and particularly along the channel activation pathway, suggests a novel mechanism of competitive inhibition.}, keywords = {Setron, anti-emetic, ion channels}, journal = {eLife}, issn = {2050-084X}, publisher = {eLife Sciences Publications, Ltd}, } 管家婆期期准免费资料精选