X-ray structures define human P2X(3) receptor gating cycle and antagonist action

Area of Science:

• Structural biology
• Molecular pharmacology
• Ion channel research

Background:

• P2X receptors are crucial ATP-gated ion channels involved in cardiovascular, neuronal, and immune functions.
• Despite their importance and therapeutic potential, human P2X receptor structures and gating mechanisms remain largely unknown.

Purpose of the Study:

• To elucidate the structural basis of human P2X3 receptor function, including gating, desensitization, and antagonism.
• To provide high-resolution structures of the human P2X3 receptor in various functional states.

Main Methods:

• X-ray crystallography was employed to determine the structures of the human P2X3 receptor.
• Structures were obtained in apo/resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized, and antagonist-bound/closed states.

Main Results:

• The open state structure reveals a 'cytoplasmic cap' motif stabilizing the pore and unique cytoplasmic fenestrations.
• Competitive antagonists TNP-ATP and A-317491 were observed to stabilize the resting state, elucidating inhibition mechanisms.
• Structures illustrate key conformational changes underlying P2X receptor gating and desensitization.

Conclusions:

• The determined structures provide unprecedented insight into human P2X3 receptor conformational dynamics.
• These findings lay the groundwork for developing novel pharmacological agents targeting P2X receptors.