PhD iCASE with Merck (USA): allosteric modulation of P2X ion channels

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P2X receptors are ligand-gated ion channels activated by extracellular adenosine 5'-triphosphate (ATP). In mammals, fast biological effects of ATP are mediated by P2X receptors during neurotransmission, response to painful stimuli and regulation of blood pressure. The human genome encodes 7 P2X receptors (P2X1-7). P2X receptors are trimeric, formed by the assembly of 3 pore-forming subunits that form a cation-selective pore gated by extracellular ATP. The ATP binding site (orthosteric site) lies between subunits and is highly structurally conserved. Drug-like compounds that bind to the orthosteric site are therefore unlikely to offer receptor subtype specificity. Conversely, allosteric sites are under low evolutionary pressure and are likely to display structural diversity between receptor subtypes. Despite some progress, the predictive identification of allosteric sites remains challenging.A collaboration with Merck will allow for investigation of known small molecule allosteric modulators of P2X eceptors for empirical identification of allosteric sites within P2X receptors. The project will employ patch-clamp electrophysiology, molecular modelling, calcium imaging, mutagenesis and high-throughput screening to elucidate the molecular basis for allosteric modulation of P2X receptor subunits.