Examination of intramolecular interactions between residues of the cys-loop GABA receptor Hco-UNC-49 from Haemonchus contortus

Haemonchus contortus is a parasitic nematode known to infect ruminant animals such as sheep, goats and cattle. Despite several different anthelmintic drugs available to control the spread of this infection, H. contortus has shown resistance to all of them. In order to combat the infection, a novel drug target must be found and characterized. Hco-UNC-49 is unique parasitic nematode γ-aminobutyric acid (GABA) gated chloride channel that may prove to be a novel drug target. The objective of this thesis was to characterize intramolecular interactions of Hco-UNC-49B. Two sets of oppositely charged residues were chosen based on their proximity to each other in a model of Hco-UNC-49 generated using the C. elegans GluCl crystal structure as a template. These residues are predicted to form salt bridges in Hco-UNC-49B which may contribute to structure, function, and molecular interactions with ligands. Each amino acid was mutated to an alanine, followed by a mutation to a similar charged amino acid, and finally a swap between the two residues encompassing the salt bridge. It was found that all residues chosen were critical for receptor function to varying degrees. R159 may be interacting with D83 by either a hydrogen or ionic interaction. Overall, this thesis revealed a probable salt bridge that may be conserved among GABA receptors, as well as one novel interaction that may be unique to Hco-UNC-49. These results expose similarities and differences between Hco-UNC-49 and mammalian GABA receptors that may be vital for the creation of new anthelmintics.

Name thesis:degree_name

Master of Science (MSc)

Discipline thesis:degree_discipline

Applied Bioscience

Grantor

University of Ontario Institute of Technology

Year dc:date.issued

2016

Author dc:creator

• Foster, Josh G.

Advisor dc:contributor.advisor

• Forrester, Sean

• H.contortus
• Ligand-gated chloride channel
• Salt bridge
• GABA
• Electrophysiology

Language dc:language.iso

en

Handle dc:identifier.uri

https://hdl.handle.net/10155/695

OAI identifier oai:identifier

oai:ontariotechu.scholaris.ca:10155/695