Abstract
P2X receptors are non-selective cation channels gated by extracellular ATP, and the P2X7 receptor subtype plays a crucial role in the immune and nervous systems. Altered expression and dysfunctions of P2X7 receptors caused by genetic deletions, mutations, and polymorphic variations have been linked to various diseases, such as rheumatoid arthritis and hypertension. Despite the availability of crystal structures of P2X receptors, the mechanism of competitive antagonist action for P2X receptors remains controversial. Here, we determine the crystal structure of the chicken P2X7 receptor in complex with the competitive P2X antagonist, TNP-ATP. The structure reveals an expanded, incompletely activated conformation of the channel, and identified the unique recognition manner of TNP-ATP, which is distinct from that observed in the previously determined human P2X3 receptor structure. A structure-based computational analysis furnishes mechanistic insights into the TNP-ATP-dependent inhibition. Our work provides structural insights into the functional mechanism of the P2X competitive antagonist.
Highlights
P2X receptors are non-selective cation channels gated by extracellular ATP, and the P2X7 receptor subtype plays a crucial role in the immune and nervous systems
We report the crystal structure of the chicken P2X7 receptor in complex with TNP-ATP, providing clarification of the TNP-ATP recognition by the P2X7 receptor, as well as precise structural interpretations of P2X7 mutations and single-nucleotide polymorphisms (SNPs) (Figs. 2 and 3; Supplementary Fig. 4)
The recently determined panda P2X7 (pdP2X7) structures showed that P2X7 receptors have the subtypespecific inter-subunit cavity formed by the upper body domains between two neighboring subunits, and that ATP binding to P2X7 receptors induces the closure of this inter-subunit cavity and the following downward movement of the head domain toward the ATP binding pocket[24]
Summary
P2X receptors are non-selective cation channels gated by extracellular ATP, and the P2X7 receptor subtype plays a crucial role in the immune and nervous systems. We determine the crystal structure of the chicken P2X7 receptor in complex with the competitive P2X antagonist, TNP-ATP. The structure reveals an expanded, incompletely activated conformation of the channel, and identified the unique recognition manner of TNP-ATP, which is distinct from that observed in the previously determined human P2X3 receptor structure. Each subunit of the P2X receptor is composed of the large extracellular domain that contains the ATP and other ligand binding sites, the two transmembrane helices that form a non-selective cation pore, and the intracellular N- and C-termini that modulate channel gating. The calculated Kd for TNP-ATP binding is 12.26 ± 2.64 μM
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