Research at the University of Wollongong will revolve around the investigation and development of cryo-EM techniques to enable structural resolution of the interactions. Knowledge obtained by the structural work will be used iteratively to computationally model and design novel compounds.
The University of Wollongong (UOW) Molecular Horizons Node is currently seeking PhD applicants interested in the area of technology development in cryo-EM and cryo-EM on membrane proteins involved in chronic pain. The project(s) will involve exploring ways to advance each of the 3 key areas in the workflow for cryo-EM of GPCRs from enabling biochemistry, to efficiency and robustness of vitrification and imaging, through to optimised data processing and the ability to directly derive 3D conformational dynamics, as well as research around the investigation and development of cryo-EM techniques to enable structural resolution of the interactions. Knowledge obtained by the structural work will be used iteratively to computationally model and design novel compounds. The research project at the University of Wollongong will focus on the areas outlined below:
The Adams group at the University of Wollongong has identified a group of analgesic peptides (α-conotoxins), from marine cone snails, that target the γ- aminobutyric acid B receptor (GABABR). This modulates voltage-gated calcium channels and, through G protein signalling, G protein inwardly rectifying potassium (GIRK) channels, both known analgesia producing targets. Although several GPCR structures have been determined, the heterodimeric nature of the GABABR has hindered efforts for its structural elucidation. Cryo-EM is ideally suited to circumvent hurdles associated with recombinant protein production and heteromeric arrangement. The apo- and holo- states of GABABR in the absence and presence of the analgesic α-conotoxin Vc1.1 would provide the first atomistic picture of GABABR and will provide details on the molecular mechanism of its action and modulation by Vc1.1. Prof Adams has already shown that Vc1.1 binds to a site distinct from the classic GABABR agonists, GABA and Baclofen. Novel compounds will be functionally screened in the high throughput (HT) patch clamp instrument SynchroPatch384PE housed at Illawarra Health and Medical Research Institute (IHMRI).
Investigating ion channels that control neuronal excitability in health and disease:
Neurons communicate with one another via the flow of ions across membranes, mediated by ion channel activity that coordinates action potential firing. The likelihood and rate of firing is underpinned by neuronal excitability, which can become dysregulated in diseases, such as epilepsy, pain and motor neuron disease. This research will investigate the structures of ion channels that are central to the control of neuronal excitability in health and disease. The knowledge gathered from this study will be crucial in improving current drugs and designing novel ones for treating neurological disorders.
Determining the 3D structure of Salmonella typhimurium voltage-gated potassium channel:
The interplay between bioelectrical and biochemical signals at the intra- and intercellular levels determines physiological function. These signals are shaped by the movement of sodium (Na+), potassium (K+) and calcium (Ca2+) ions into and out of cells. Selective ionic passage through cell membranes occurs via channels formed by membrane proteins. Channels that open and close in response to changes in the transmembrane voltage are called voltage gated ion channels (VGICs). VGICs are typically associated with fast electrical signalling in multicellular organisms, whilst VGICs are abundantly found in bacteria. Despite their abundance in mesophilic bacteria, the only available prokaryotic Kv channel structure comes from a hyperthermophilic archaea Aeropyrum pernix (KvAP), which may not be representative of mesophilic bacterial Kv channels.
Salmonella typhimurium (STM) is a mesophilic bacterium, a pathogen that causes gastroenteritis and typhoid fever. Relatively little is known about STM’s signalling or specific metabolic requirements yet transport and maintenance of K+ homoeostasis are important for Salmonella’s extracellular and invasive strategies. We propose to determine the molecular 3D structure of Salmonella’s KvSTM channel by cryo-EM, providing the first mesophilic bacterial Kv channel structure. This structural insight will complement functional and physiological research to elucidate features underlying STM’s fitness. Furthermore, comparing KvSTM to its eukaryotic counterparts may enable the development of species-specific Kv modulators thereby improving the therapeutic window of currently used drugs.
This project is part of the Australian Research Council (ARC) Training Centre for cryo-electron Microscopy of Membrane Proteins (CCeMMP) are looking for highly motivated, passionate and competitive PhD candidates to join the Doctoral Training Program. Successful candidates will be offered a four-year fully funded PhD position with a strong industry focus, and will work within the Centre at the University of Wollongong located in Australia. The Centre is a collaboration between Nodes led by the Institute of Pharmaceutical Sciences at Monash University, and in partnership with The University of Melbourne (Bio21 Institute), University of Wollongong (Molecular Horizons) and the Walter and Eliza Hall Institute (WEHI).
This opportunity will provide graduates with invaluable experience in a brand new world-class research facility and the opportunity to network with industry partners for a year during their studies.
This training Centre is funded by the Australian Research Council. The projects are funded by the industry partners.
Enquiries email name and address:
All queries to be directed to Dr Jackie How at email@example.com
For more information on the PhD program and the research project, please register to attend our PhD Information Night at 5:30pm AEDT 28th of September 2021. To register: https://www.eventbrite.com.au/e/ccemmp-hdr-night-2021-tickets-168521509371
Application Web Page:
To apply, please go to https://ccemmp.org/training/opportunities/.