Comparative models of P2X2 receptor support inter-subunit ATP-binding sites

Area of Science:

• Biophysics
• Structural Biology
• Neuroscience

Background:

• ATP-gated P2X receptors (P2XRs) are ligand-gated ion channels (LGICs) with an assumed trimeric structure, but lack high-resolution experimental structures.
• The recent crystal structure of acid-sensing ion channel 1 (ASIC1) provided a template due to shared membrane topology, despite low sequence similarity.

Purpose of the Study:

• To develop comparative models of the P2X(2) receptor (P2X2R) to elucidate its structure and gating mechanism.
• To overcome the challenge of low sequence homology between P2XRs and ASIC1 by utilizing secondary structure predictions.

Main Methods:

• Comparative modeling of P2X2R using the ASIC1 crystal structure as a template.
• Incorporation of known disulfide bridge arrangements to constrain the models.
• Validation against existing cross-linking experimental data.

Main Results:

• Developed validated comparative models of P2X2R that are consistent with experimental data.
• The models support the existence of inter-subunit ATP-binding sites.
• One refined model offers new structural insights into a plausible gating mechanism for P2XRs.

Conclusions:

• The developed models provide a structural framework for understanding P2X2R function.
• These findings encourage further experimental investigation into P2XR gating mechanisms.
• The study highlights the utility of comparative modeling in the absence of direct structural data for LGICs.