Understanding the basic of subtype selectivity at muscarinic acetylcholine receptors
Understanding how chemicals outside the cell signal to proteins inside the cell, how this results in biological responses, and how these responses can be modulated by synthetic molecules targeting cellular proteins remains a major challenge in the life sciences. G protein-coupled receptors (GPCRs) are the largest group of cell surface signalling proteins and are also the largest class of drug target. Despite their importance, much remains to be learned about the regulation of GPCRs by small molecules, especially with regards to developing chemical probes that can selectively target one GPCR while sparing others. To address this gap our laboratory focuses on novel regions on these proteins, termed allosteric sites, which are spatially distinct from the orthosteric site commonly recognized by natural hormones, neurotransmitters and drugs, highly conserved between subtypes of a given GPCR class, thus accounting for lack of selectivity of most contemporary GPCR-targeting molecules. Despite the discovery of a number of synthetic molecules, called allosteric modulators, that bind to allosteric sites in a more selective fashion than classic orthosteric activators (agonists) or blockers (antagonists), the molecular mechanisms that determine allosteric drug selectivity remain largely unknown. Through the use of mutagenesis, radioligand binding, various functional assays and fluorescence-based studies, the project aims at unravelling the mechanisms of action of several selective and non-selective allosteric modulators of an important family of GPCRs, the muscarinic acetylcholine receptors.
Our research project falls under the Lab Rotation option