TY - JOUR TI - High-resolution structures of multiple 5-HT3AR-setron complexes reveal a novel mechanism of competitive inhibition AU - Basak, Sandip AU - Kumar, Arvind AU - Ramsey, Steven AU - Gibbs, Eric AU - Kapoor, Abhijeet AU - Filizola, Marta AU - Chakrapani, Sudha A2 - Czajkowski, Cynthia M A2 - Boudker, Olga A2 - Czajkowski, Cynthia M VL - 9 PY - 2020 DA - 2020/10/16 SP - e57870 C1 - eLife 2020;9:e57870 DO - 10.7554/eLife.57870 UR - https://doi.org/10.7554/eLife.57870 AB - 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. KW - Setron KW - anti-emetic KW - ion channels JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER - 管家婆期期准免费资料精选