Research

Alexander Swan

Biophysical and structural characterisation of the ineraction between the Popeye domain containg 1 (POPDC1) protein and small molecule ligands - towards a treatment for atrial fibrillation

Alexander Swan - MRes

Abstract

The Popeye domain containing (POPDC) family encodes a novel class of cyclic adenosine monophosphate (cAMP) effector proteins and acts as a hub gene in atrial fibrillation (AF). POPDC1 has a homeostatic role and displays a large number of protein-protein interactions (PPIs) involved in the generation and conduction of action potentials. POPDC1 interacts with ion channels such as SCN5A or TREK-1 involved in action potential generation and connexins such as Cx43, which ensure electrical coupling between cardiac myocytes. POPDC1 not only binds cAMP but also interacts with phosphodiesterases, which are important for cAMP compartmentalisation. The high- affinity cAMP-binding domain of POPDC1 is unique and we have identified an array of small molecules, which selectively bind to POPDC1 but not to other cAMP-binding proteins. In this project, we plan to structurally characterise the binding interactions of these lead compounds using NMR and SPR methods aided by isotopic ligand synthesis with the aim to lay the foundation for the development of more selective and potent small molecule modulators of this important protein family.