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|Title: ||ρ GABAC Receptors: Modelling and Structure Function of the Orthosteric Binding Site|
|Authors: ||Naffa’a, Moawiah Moh’d Said|
|Issue Date: ||27-Mar-2015|
|Publisher: ||University of Sydney|
Faculty of Pharmacy
|Abstract: ||The GABA receptors are membrane receptors that activated by GABA. A subclass of ligand-gated ion channels were identified, insensitive to ligands that typically affected GABAA and GABAB receptors, were classed as ρ1GABAC.
Homology modelling based on available templates affords the best method to gain knowledge about the structure of the GABA binding site of ρGABAC receptors. ρ1GABAC homology models were generated based on AChBP, GLIC, ELIC, GABAA β3 and GluClα templates. The ρ1 model based on GluCl and refined with other models based on other templates was used to explore the GABA pose and to identify several residues involved in potential interactions.
Three hydrophilic residues (Ser168, Ser243 and Thr244) line the orthosteric binding site of ρ1 receptors were studied by point mutation. Thr244 is essentially residue for the channel activation that will initiate conformational changes stabilizing open conformation. Ser243 is critical in stabilizing channel states via inter-subunit interactions. Ser168 is predicted to form H-bond with ligands, suggesting a role in stabilizing either channel state.
ρ2GABAC homology model were generated based on GluCl. The activation and co-operative/inhibition effects of three sets of partial agonists were discussed in terms of their efficacy and magnitude of additive and inhibitory effects. The intersubunit selectivity with ρ1GABAC is recognized.|
|Type of Work: ||PhD Doctorate|
|Type of Publication: ||Doctor of Philosophy Ph.D.|
|Appears in Collections:||Sydney Digital Theses (Open Access)|
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|NAFFAA Moawiah - Final Thesis.pdf||Final Thesis||6.69 MB||Adobe PDF|
|NAFFAA Moawiah - Lodgement Form.pdf||Student Logement Form and Faculty Checklist||1.7 MB||Adobe PDF|
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