Poster Presentation 2014 International Biophysics Congress

Using 3D based phylogenetics to explore the relationship between Cys-loop receptor binding sites (#441)

Troels E Sorensen 1 2 , Thomas Balle 2 , Bente Frølund 1 , Flemming S Jørgensen 1
  1. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
  2. University of Sydney, Sydney, NSW, Australia

The large range of Cys-loop receptor subunits, gives rise to a wide variety of interfaces and thus potential binding sites. However the difficulty of attaining selectivity has made studying a given binding site and its function problematic. To better understand the relationship between different binding sites phylogenetics methods has been used before1, however these have used a 1D approach focusing on the entire subunit sequence, in contrast the present work has focused on only the binding site residues, as determined via 3-dimensional structure modelling, since it has been shown that function can rely on only a few residues in the binding site.2 A phylogenetic tree was constructed based on similarity between different nAChR binding sites, and ligand affinity data was then mapped to the tree, thereby enabling the study of the relationships between ligands and interfaces. The tree was validated on a number of novel interfaces using compounds such as the stoichiometry selective NS92833. The phylogenetic tree allows the study of interfaces beyond just the well-known interfaces and as such can potentially be used to discover previously unknown binding sites, such as the α4α4 interface2. Furthermore it allows us to better understand the structural reasons behind the presence or lack of selectivity, and help identify and optimize new lead compounds.

  1. Nys, M., Kesters, D. & Ulens, C. Structural insights into Cys-loop receptor function and ligand recognition. Biochem. Pharmacol. 86, 1042–53 (2013).
  2. Harpsøe, K. et al. Unraveling the high- and low-sensitivity agonist responses of nicotinic acetylcholine receptors. J. Neurosci. 31, 10759–66 (2011).
  3. Timmermann, D. B. et al. Augmentation of cognitive function by NS9283, a stoichiometry-dependent positive allosteric modulator of α2- and α4-containing nicotinic acetylcholine receptors. Br. J. Pharmacol. 167, 164–82 (2012).