XPR1 is characterized by a unique architecture that includes a transmembrane domain (TMD) and a cytoplasmic SPX domain. The TMD is composed of multiple transmembrane helices that form a channel-like structure. Recent cryo-electron microscopy (cryo-EM) studies have revealed various conformational states of XPR1, including inactive (closed) and active (open) forms, as well as intermediate states.[8][9] Notably, XPR1 features dual binding sites for Inositol phosphate(IPs) and inositol pyrophosphates (PP-IPs), which regulate its activity.
Electrophysiological studies on XPR1 showed that XPR1 functions primarily as a PP-IPs gated Pi channel,[9] playing a pivotal role in preventing the accumulation of excess intracellular phosphate, which can lead to metabolic disorders. It responds to the cellular levels of IPs and PP-IPs, with PP-IPs acting as more potent activators of XPR1 compared to IPs. The binding of these signaling molecules induces conformational changes in XPR1, facilitating the opening of the channel and allowing phosphate ions to exit the cell.
