Structural information is essential for understanding protein function at a molecular level. This information is invaluable for both basic and applied science. However, many targets have remained unexplored due to the challenges associated with determining protein structures.

This pilot project aims to obtain the molecular structure of a physiologically relevant membrane protein, either in isolation or in complex with potential pharmacological compounds. We will focus on ion channel target family of SK-channels, which is essential for human health and a highly attractive target for the treatment of both acute and chronic atrial fibrillation. Breakthroughs recently achieved by the Gourdon laboratory will be utilised in conjunction with the proposed infrastructure facilities.

This project aims to gain a spatial understanding of how SK channels bind to novel, promising drug targets in their soluble domain, known as the EF hand. The focus will be on using FragMAX to prepare and evaluate protein-ligand crystals to identify novel binders that manipulate the EF-motif binding of the physiological regulator calmodulin. This knowledge will guide cryo-EM experiments on full-length proteins. Positive results have the potential to assist ongoing development of current Phase-II clinical therapeutic targets conducted by Acesion Pharma A/S for the treatment of atrial fibrillation aiding in cardiovascular health.