Structural Insights into Divalent Cation Modulations of ATP-Gated P2X Receptor Channels

• The ATP- and Zn2+-bound structure of an invertebrate P2X receptor is determined
• Two distinct metal binding sites in the extracellular region are identified
• The first site, located at the trimer interface, contributes to Zn2+ potentiation
• The second site is coupled with ATP binding for regulation by Mg2+

SummaryP2X receptors are trimeric ATP-gated cation channels involved in physiological processes ranging widely from neurotransmission to pain and taste signal transduction. The modulation of the channel gating, including that by divalent cations, contributes to these diverse physiological functions of P2X receptors. Here, we report the crystal structure of an invertebrate P2X receptor from the Gulf Coast tick Amblyomma maculatum in the presence of ATP and Zn2+ ion, together with electrophysiological and computational analyses. The structure revealed two distinct metal binding sites, M1 and M2, in the extracellular region. The M1 site, located at the trimer interface, is responsible for Zn2+ potentiation by facilitating the structural change of the extracellular domain for pore opening. In contrast, the M2 site, coupled with the ATP binding site, might contribute to regulation by Mg2+. Overall, our work provides structural insights into the divalent cation modulations of P2X receptors.

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