Application of cryo-EM to understanding of channels and receptors involved in chronic pain

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. Research at the Wollongong node 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. Novel compounds will be functionally screened in the high throughput (HT) patch clamp instrument SynchroPatch384PE housed at IHMRI.

  

This work will be completed with the University of Wollongong Node.