AI Article Synopsis
- P2X receptors are ion channels in mammalian cell membranes that open when ATP binds to them, but the specific sequence of changes leading to this opening is not fully understood.
- The research uses umbrella sampling simulations to explore how ATP binds to the P2X4 receptor, revealing a metastable state that helps facilitate this binding.
- This new understanding suggests a revised mechanism for how ATP is captured by P2X4 receptors, involving stabilizing interactions with positively charged residues.
Article Abstract
P2X receptors are a family of trimeric cationic channels located in the membrane of mammalian cells. They open in response to the binding of ATP. The differences between the closed and open structures have been described in detail for some members of the family. However, the order in which the conformational changes take place as ATP enters the binding cleft, and the residues involved in the intermediate stages, are still unknown. Here, we present the results of umbrella sampling simulations aimed to elucidate the sequence of conformational changes that occur during the reversible binding of ATP to the P2X4 receptor. The simulations also provided information about the interactions that develop in the course of the process. In particular, they revealed the existence of a metastable state which assists the binding. This state is stabilized by positively charged residues located in the head domain of the receptor. Based on these findings, we propose a novel mechanism for the capture of ATP by P2X4 receptors.
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| http://dx.doi.org/10.1021/acs.jcim.9b00856 | DOI Listing |
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