title: A comprehensive study on the 5-hydroxytryptamine(3A) receptor binding of agonists serotonin and m-chlorophenylbiguanidine.
abstract: Serotonin type 3 receptors (5-HT(3)R) are members of the ligand gated ion channel receptor family. In this study, the interactions of the agonists serotonin (5-HT) and m-chlorophenylbiguanidine (mCPBG) at the binding site of the 5-HT(3A)R were investigated at an atomic level. Site-directed mutagenesis studies in Loop B and E along with our earlier published results from mutations within Loops A, C, and D provide comprehensive data on the interaction of 5-HT and mCPBG with 5-HT(3A)Rs. Using this data we have constructed a refined homology model of the 5-HT(3A)R that considers all of the available experimental data. 5-HT and mCPBG were docked into the newly constructed homology model and the amino acid residues critical in binding of these agonists were compared and analyzed. Our docking results reveal many similar binding interactions for 5-HT and mCPBG. Namely, residues THR181, TRP183, PHE226, ILE228, TYR234 and GLU129 were all found to play key roles in binding of both 5-HT and mCPBG. However, the results also revealed two important differences that exist between the interactions of the two agonists. In our model, a hydrogen bond is formed between the indole hydrogen of 5-HT and the residue TYR153. This interaction is not present in the case of mCPBG. Conversely, a hydrogen bond exists between SER182 and a protonated nitrogen of mCPBG, which does not exist in 5-HT. Our modeling results were found to be in accordance with experimental data.
authors.affiliation: Virtua Drug Ltd, Budapest, Hungary.
authors.forename: Eszter
authors.initials: E
authors.lastname: Hazai
authors.forename: Prasad
authors.initials: P
authors.lastname: Joshi
authors.forename: Edward C
authors.initials: EC
authors.lastname: Skoviak
authors.forename: Asha
authors.initials: A
authors.lastname: Suryanarayanan
authors.forename: Marvin K
authors.initials: MK
authors.lastname: Schulte
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Bikadi
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D006146:Guanidines / Q000737:chemistry* / Q000494:pharmacology; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009865:Oocytes / Q000187:drug effects; D018408:Patch-Clamp Techniques; D044406:Receptors, Serotonin, 5-HT3 / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D058827:Serotonin 5-HT3 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000737:chemistry* / Q000494:pharmacology; D014982:Xenopus laevis
chemical_list: D006146:Guanidines; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D017366:Serotonin Receptor Agonists; C495409:m-chlorophenylguanidine