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dc.contributor.authorAtaian, Yeganeh
dc.date.accessioned2018-06-13T23:34:26Z
dc.date.available2018-06-13T23:34:26Z
dc.date.issued2018-05
dc.identifier.urihttp://hdl.handle.net/11122/8644
dc.descriptionThesis (Ph.D.) University of Alaska Fairbanks, 2018en_US
dc.description.abstractAcetylcholine-binding protein (AChBP) is a water-soluble novel protein with a high sequence similarity (15-30% identity) to ligand-gated ion channel (LGIC) receptors. The crystal structure of AChBP is used to study the extracellular domain of the pentameric LGICs such as nicotinic acetylcholine receptors (nAChRs) and 5-hydroxytryptamine type 3 receptors (5-HT₃Rs); and homology models have been developed to study receptor-ligand interactions. The 5-HT₃ serotonin receptors are potential therapeutic targets for multiple nervous system disorders such as alcohol and drug dependence, anxiety, depression, schizophrenia, sleep, cognition, memory, and chemotherapy-induced and post-operative nausea and vomiting. Therefore, the ligands that target the 5-HT₃Rs are considered powerful therapeutic agents. As such, 5-HT₃ serotonin receptors have been the targets of drug discovery efforts. The main objective of the current protein engineering project was to develop a soluble serotonin-binding protein using AChBP, which would mimic the specificity of the native 5-HT₃ serotonin receptor. Once developed, this soluble protein would be used as a model to design an array of receptors, which could be placed on biosensors for high-throughput drug screening (HTDS). The results of site-directed mutagenesis of AChBP demonstrated that mutation of certain AChBP residues to its equivalent in serotonin resulted in an increased affinity of AChBP for serotonin ligands, and that each individual mutation increased the affinity of AChBP to a certain degree. It indicates that this approach is going in the right direction but multiple mutations will probably be needed to get to an AChBP whose affinity is equivalent to wild-type serotonin. In addition, the most significant changes appeared to be in the C-loop as it produced the largest increase in affinity of AChBP for serotonin agonists. The results also support the proposed C-loop closure model for the receptor, and based on data presented here, a new alignment of the C-loop is suggested.en_US
dc.language.isoen_USen_US
dc.subjectAcetylcholineen_US
dc.subjectReceptorsen_US
dc.subjectSerotoninen_US
dc.subjectAgonistsen_US
dc.subjectAntagonistsen_US
dc.subjectLigand binding (Biochemistry)en_US
dc.subjectReceptor-ligand complexesen_US
dc.titleDevelopment of acetylcholine-binding protein (AChBP) as a biosensor for serotonin ligandsen_US
dc.typeThesisen_US
dc.type.degreephden_US
dc.identifier.departmentDepartment of Chemistry and Biochemistryen_US
dc.contributor.chairSchulte, Marvin
dc.contributor.chairDuffy, Lawrence
dc.contributor.committeeKuhn, Thomas
dc.contributor.committeeBult-Ito, Abel
refterms.dateFOA2020-03-05T16:13:04Z


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