Poster Presentation 2014 International Biophysics Congress

Computational study of conotoxin GID interaction with α7 and α4β2 nicotinic receptor subtypes    (#578)

Abishek Suresh 1 , Andrew Hung , David Adams
  1. Applied Sciences, RMIT University, Melbourne, VIC, Australia

Neuronal nicotinic receptors(nAChr) belong to a group of pentameric ligand-gated ion channels. Each receptor contains a group of 5 subunits arranged around a central ion pore. Ligand-binding activation of these receptors causes ion-channel opening. The α7/α4β2 neuronal receptor sub-types, prevalent in the CNS and cortex of the brain are responsible for a number of neuro-physiological functions, more importantly, the release of neuro-receptors- dopamine, serotonin etc. Neuronal nAChrs have been implicated in various neuro-degenerative disorders such as Alzheimer’s and Parkinson’s disease. However, current treatment is more symptomatic. Conotoxins (source: Conus snail) target specific muscular/neuronal receptors acting as agonists/antagonists. We use molecular dynamics simulations to understand the behaviour of the α-conotoxin GID within the respective α7 and α4β2 ligand binding pockets. In support of previous studies showing greater GID activity towards the α7 than the α4β2 receptor subtype, our results show that GID undergoes conformational shifts to adapt itself into the α7 c-loop binding pocket and fails to do the same at the α4β2. By comparing the number of contacts made by individual GID residues with the respective receptor pocket, we identify and propose various mutations to GID that will enhance its specificity to the α4β2 receptor pocket. Our study identified possible mutation sites at GID[S7, R12, V13, N14, O16, V18].     

  1. Millard EL, Nevin ST, Loughnan ML, Nicke A, Clark RJ, Alewood PF, Lewis RJ, Adams DJ, Craik DJ, Daly NL. (2009) Inhibition of neuronal nicotinic acetylcholine receptor subtypes by a-conotoxin GID and analogues. J. Biol. Chem. 284, 4944-4951.