Prediction of 5-HT3 Receptor Agonist-Binding Residues Using Homology Modeling

Abstract

5-HT(3) receptors demonstrate significant structural and functional homology to other members of the Cys-loop ligand-gated ion channel superfamily. The extracellular domains of these receptors share similar sequence homology (approximately 20%) with Limnaea acetylcholine binding protein, for which an x-ray crystal structure is available. We used this structure as a template for computer-based homology modeling of the 5-HT(3) receptor extracellular domain. AutoDock software was used to dock 5-HT into the putative 5-HT(3) receptor ligand-binding site, resulting in seven alternative energetically favorable models. Residues located no more than 5 A from the docked 5-HT were identified for each model; of these, 12 were found to be common to all seven models with five others present in only certain models. Some docking models reflected the cation-pi interaction previously demonstrated for W183, and data from these and other studies were used to define our preferred models.

A Role for the β1-β2Loop in the Gating of 5-HT3Receptors

“…1). The resulting model was combined with a 5-HT 3A subunit extracellular domain (ECD) model (Reeves et al, 2003) in Deepview 3.7b (Swiss Institute of Bioinformatics). The domains were aligned electronically by minimizing the distance between ␣-carbons for the single residue common to both domains (P211 from the ECD structure).…”

Insight in nAChR subtype selectivity from AChBP crystal structures

“…Hence, CLR modeling strategies have heavily relied on the X-ray structures of AChBPs and their complexes together with the structure of the Torpedo nAChR [24][25][26][27]. The availability of the recently solved X-ray structure of the monomeric mouse α 1 nAChR subunit in complex with α-Bungarotoxin [28] indeed illustrates that AChBP constitutes a very good model for studying nAChRs, especially when considering the high degree of structural similarity between the α 1 and AChBP structures; mouse α 1 nAChR subunit superposes to carbamylcholine-bound LsAChBP with an r.m.s.…”

In silico investigation into the interactions between murine 5-HT3 receptor and the principle active compounds of ginger (Zingiber officinale)

“…[5] Prior to this, structural studies had relied on homology models using templates from other CYS loop receptors. [31] (sub-nanomolar), possibly stabilizing a non-conducting conformation. Despite the relatively low resolution, knowledge of the three-dimensional structure has facilitated these in silico investigations with the aim of investigating the binding characteristics of the primary compounds within ginger on the 5-HT3 receptor.…”