Dr. Margot Ernst

Subtype specific targeting of GABAA receptors.
It is commonly agreed that subtype selective modulators of GABAA receptors are potentially useful for therapy and research. During the first funding period of this program, great progress was made both in our research and in the scientific community. Together with the Mihovilovic and Ecker labs, we obtained ligands with better subtype selectivity. We can now specifically target α6β3γ2 receptors and α5βγ2 receptors. Structural insight was advanced by the release of the first X-ray crystallographic structure of a GABAA receptor. Together with the Hering lab, a ligand was mapped to the "ivermectin" site from a homologous protein for which an ivermectin bound state has been crystallized. Despite these milestone accomplishments, highly selective modulators are still missing for most receptor subtypes. In this thesis project the molecular mechanisms that govern subtype selectivity will be studied by a combined in silico and experimental approach. In silico work will be done with a partner lab, and in this thesis project, experimental testing of structural hypotheses will be performed. Based on the model structures from docking studies of selective ligands and unselective analogues from the computational partner, mutants will be designed that should eliminate or introduce selective interaction (gain- and loss- of function approach, "diagnostic" mutations). The mutated receptors will then be investigated with functional studies using two electrode voltage clamp electrophysiology and binding assays. The functional data will thus verify, improve, or revise the hypotheses.