Title : X-ray structures define human
P2X( 3)
receptor gating cycle and antagonist action
Abstract :
- P2X receptors are trimeric, non-selective cation channels activated by ATP that have important roles in the cardiovascular, neuronal and immune systems
- Despite their central function in human physiology and although they are potential targets of therapeutic agents, there are no structures of human P2X receptors
- The mechanisms of receptor desensitization and ion permeation, principles of antagonism, and complete structures of the pore-forming transmembrane domains of these receptors remain unclear
- Here we report X-ray crystal structures of the human P2X3 receptor in apo /resting, agonist-bound/open-pore, agonist-bound/closed-pore/desensitized and antagonist-bound/closed states
- The open state structure harbours an intracellular motif we term the 'cytoplasmic cap', which stabilizes the open state of the ion channel pore and creates lateral, phospholipid-lined cytoplasmic fenestrations for water and ion egress
- The competitive antagonists TNP- ATP and A-317491 stabilize the apo /resting state and reveal the interactions responsible for competitive inhibition
- These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents