Prediction of 5-HT3 receptor agonist-binding residues using homology modeling |
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Authors: | Reeves David C Sayed Muhammed F R Chau Pak-Lee Price Kerry L Lummis Sarah C R |
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Affiliation: | Department of Biochemistry, University of Cambridge, Cambridge CB2 1AG, United Kingdom. |
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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. |
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Keywords: | 5-HT3, 5-hydroxytryptamine3 LGIC, ligand-gated ion channel ACh, acetylcholine AChBP, acetylcholine binding protein nAChR, nicotinic acetylcholine receptor GABA, gamma-amino butyric acid ECD, extracellular domain |
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