Exploring a potential palonosetron allosteric binding site in the 5-HT(3) receptor
作者： Marta Del Cadia , Francesca De Rienzo , David A. Weston , Andrew J. Thompson , Maria Cristina Menziani
DOI: 10.1016/J.BMC.2013.09.028
关键词: Allosteric regulation 、 Docking (molecular) 、 Chemistry 、 Palonosetron 、 Binding site 、 Receptor antagonist 、 Homomeric 、 Biochemistry 、 Mechanism of action 、 Radioligand
摘要: Palonosetron (Aloxi) is a potent second generation 5-HT3 receptor antagonist whose mechanism of action not yet fully understood. acts at the binding site but recent computational studies indicated other possible sites in extracellular domain. To test this hypothesis we mutated series residues 5-HT3A subunit (Tyr73, Phe130, Ser163, and Asp165) 5-HT3B (His73, Glu170, Tyr143) that were previously predicted by silico docking to interact with palonosetron. Homomeric (5-HT3A) heteromeric (5-HT3AB) receptors then expressed HEK293 cells determine potency palonosetron using both fluorimetric radioligand methods function ligand binding, respectively. The data show substitutions have little or no effect on inhibition 5-HT-evoked responses binding. In contrast, orthosteric abolish Overall, support for classic pocket between two subunits allosteric identified modelling docking.
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