Rustamov, Khondamir R;
Makhmudov, Albert R;
Ikromova, Fozila R;
Vetrova, Ekaterina A;
Vinokurov, Andrey Y;
Razzokov, Jamoliddin I;
Abramov, Andrey Y;
(2025)
The molecular mechanism of P2Y1 receptor activation by inorganic polyphosphates.
Archives of Biochemistry and Biophysics
, 772
, Article 110555. 10.1016/j.abb.2025.110555.
![[thumbnail of polyP-P2Y1R.pdf]](https://discovery.ucl.ac.uk/style/images/fileicons/text.png) |
Text
polyP-P2Y1R.pdf - Accepted Version Access restricted to UCL open access staff until 22 July 2026. Download (3MB) |
Abstract
P2Y1 receptors (P2Y1Rs) are metabotropic purinoreceptors that can be activated primarily by ADP and, to a lesser extent, by ATP. Recently it was demonstrated that P2Y1R 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 P2Y1R, the precise molecular mechanisms underlying the activation of P2Y1R by polyP are still unclear. Here, using all-atom molecular dynamics simulations, we demonstrate that polyP binding to the inactive P2Y1R induces conformational changes of the receptor, causing its transition into the active state. Binding of polyP-14 to P2Y1R 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 P2Y1 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 P2Y1R activation.
Archive Staff Only
 |
View Item |
