Molecular Modelling of P2X receptor function

Extracellular ATP is a key signalling molecule in many physiological processes including immune response and neurotransmission. It acts on P2X receptors (P2XR), a family of ligand-gated ion channels, which are activated upon binding of extracellular ATP. P2XR activation and channel opening allows the influx of small cations into the cell hereby mediating Ca2+ signalling. The human genome encodes seven P2XR homologs (P2XR1-P2XR7) that have distinct roles and show tissue specific expression. Structurally, P2XRs form homo-trimers and hetero-trimers involving different P2XR homologs. Subunit variation provides the machinery for the modulation of cell-type specific responses to extracellular ATP. Each subunit in a P2XR trimer is characterised by a large extracellular ligand binding domain, two transmembrane helices, and N- and C-termini forming an intracellular cap domain. P2XRs work by cycling through at least three states that are to some extent structurally characterized: a closed apo state with no ATP bound, an open state formed upon binding of ATP, and a desensitized state where the ion channel is closed despite ATP still being bound. The key questions for P2X receptor function we intend to address in this project are how ATP triggers the opening of the channel, how the receptor transits through the different states upon binding and unbinding of ATP, how steric and allosteric small molecule antagonists affect different states, and how the lipid environment modulates receptor function.