title: Exploring the binding of serotonin to the 5-HT3 receptor by density functional theory.
abstract: The 5-HT3 receptor is a typical ligand-gated ion channel of the Cys-loop superfamily, which is activated by binding of serotonin (5-HT). Models of the binding site of this protein reveal potential interactions between 5-HT and Tyr143, Tyr153, and Tyr234. Here we describe a series of ab initio calculations, based on density functional theory, to assess the effects of mutating these tyrosine residues on the binding of 5-HT. A series of mutations to these tyrosines, previously studied experimentally, were tested, and the binding energies compared with the available experimental data. Our results show that Tyr153 could form a hydrogen bond with the tertiary amine of 5-HT, and that mutation in this location revealed binding energies broadly in line with experimentally determined EC50s. Tyr143 could also form a hydrogen bond, but as EC50s do not relate to binding energies, it is unlikely that such a bond is formed here. Tyr234 is quite distinct in that it may interact with 5-HT via a mixed hydrogen bond/cation-pi interaction.
authors.affiliation: Physics Department, King's College London, Strand, London WC2R 2LS, United Kingdom.
authors.forename: Claudio
authors.initials: C
authors.lastname: Melis
authors.forename: P-L
authors.initials: PL
authors.lastname: Chau
authors.forename: Kerry L
authors.initials: KL
authors.lastname: Price
authors.forename: Sarah C R
authors.initials: SC
authors.lastname: Lummis
authors.forename: Carla
authors.initials: C
authors.lastname: Molteni
mesh_terms: D019943:Amino Acid Substitution; D006860:Hydrogen Bonding; D008958:Models, Molecular; D011485:Protein Binding; D044406:Receptors, Serotonin, 5-HT3 / Q000737:chemistry / Q000378:metabolism*; D014443:Tyrosine / Q000737:chemistry*
chemical_list: D044406:Receptors, Serotonin, 5-HT3; D014443:Tyrosine