The molecular mechanism of P2Y receptor activation by inorganic polyphosphates.

P2Y receptors (P2YRs) are metabotropic purinoreceptors that can be activated primarily by ADP and, to a lesser extent, by ATP. Recently it was demonstrated that P2YR can be activated by inorganic polyphosphates (polyPs) - molecules, composed solely of orthophosphate residues and lacking a purine part. Although numerous studies have demonstrated that extracellular polyP can transmit signals to neighboring cells via activation of P2YR, the precise molecular mechanisms underlying the activation of P2YR by polyP are still unclear. Here, using all-atom molecular dynamics simulations, we demonstrate that polyP binding to the inactive P2YR induces conformational changes of the receptor, causing its transition into the active state. Binding of polyP-14 to P2YR disrupts the interaction between Asp204 and Arg310 residues, increases the solvent accessible surface area (SASA) of receptor's binding pocket and induces bulk water influx into the receptor inner region. These processes induce conformational changes in the intracellular TM helices, leading to receptor activation similar to that observed in the presence of ADP. In agreement to in silico experiments, application of the same concentrations of polyP and ADP induced calcium signal in skin fibroblasts with similar shape and amplitude. Thus, our findings establish that polyP molecules can bind to and activate P2Y purinoreceptor by molecular mechanism similar to those of its natural ligand ADP. We also propose the hypothesis that interaction of pyrophosphate part of ADP or polyphosphate with certain amino acids is a key event in P2YR activation.

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