Prediction of 5-HT3 receptor agonist-binding residues using homology modeling

• Published in: Biophysical journal Vol. 84; no. 4; pp. 2338 - 2344
• Main Authors: Reeves, David C, Sayed, Muhammed F R, Chau, Pak-Lee, Price, Kerry L, Lummis, Sarah C R
• Format: Journal Article
• Language: English
• Published: United States Biophysical Society 01-04-2003
• Subjects: Amino Acid Sequence; Binding Sites; Carrier Proteins - chemistry; Channels, Receptors, and Transporters; Computer Simulation; Extracellular Fluid - chemistry; Models, Molecular; Molecular Sequence Data; Protein Binding; Protein Conformation; Protein Structure, Tertiary; Protein Subunits; Receptors, Serotonin, 5-HT3 - chemistry; Reproducibility of Results; Sensitivity and Specificity; Sequence Alignment - methods; Sequence Analysis, Protein - methods; Sequence Homology; Serotonin Receptor Agonists - chemistry
• ISSN: 0006-3495; 1542-0086
• DOI: 10.1016/S0006-3495(03)75039-5

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.