Neurological disorders are the third leading cause of premature mortality in Europe. They are often related to dysfunctions or imbalances in signalling and regulatory processes mediated by neurotransmitter molecules. Despite extensive research, the therapeutic potential of modulating these neurotransmitter systems by the key neuromodulator glycine has largely remained unexplored. The glycine transporter 1 (GlyT1) controls the transport of the neurotransmitter glycine across neuronal membranes in the brain and represents a promising therapeutic target for several neurological disorders, including schizophrenia. However, despite extensive research, inhibitors of GlyT1 have failed in clinical studies due to low efficacy, and a successful drug candidate targeting GlyT1 has yet to come.
This project aims to overcome the limitations of classical GlyT1 inhibitors by exploiting an extracellular site on the transporter that is distinct from the glycine binding site. Using a GlyT1 construct that favours the outward-open conformational state and selective binders, as well as serial synchrotron crystallography (SSX), we will uncover the molecular determinants of the substrate-free outward-open state of the transporter. This research project will lay the groundwork for identifying new conformationally selective inhibitors as therapeutic agents targeting GlyT1 and similar transporters.
Figure “Uncovering the structural basis of a novel extracellular site for the development of next-generation GlyT1 Inhibitors”
For further information about this HALRIC pilot project, please contact:
Azadeh Shahsavar
University of Copenhagen
ash@sund.ku.dk
