OHSU researchers reveal atomic structure of a key molecular receptor

The receptor proteins of a cell’s surface are important transmitters of signals between its internal and external environments. The P2X integral membrane proteins, first defined in 1976, modulate processes as diverse as platelet activation, smooth muscle contraction, synaptic transmission, inflammation, hearing and taste, making P2X receptors important pharmacological targets.

P2X receptors are activated by ATP, a major intracellular energy source, resulting in a change in the receptor’s structure and the flow of ions such as sodium and calcium into the cell. The mechanisms of receptor desensitization and the complete structures remain unclear, but OHSU scientists have, for the first time, determined the structure of a P2X receptor in the desensitized state. The team created X-ray crystal structures of the human P2X3 receptor including in open, resting, and desensitized states. Results of their study, “X-ray structures define human P2X3 receptor gating cycle and antagonist action” were published in the journal Nature on Sept. 14, 2016.

“Before our structures, nobody understood the mechanisms by which the receptor opened its pore and then transitioned to a desensitized state,” said lead author Steven Mansoor, M.D., Ph.D., a cardiology fellow in OHSU’s Knight Cardiovascular Institute and Vollum Institute.

“It’s a lot easier to make a new key if you know what the lock looks like,” said corresponding author Eric Gouaux, Ph.D., a senior scientist in the OHSU Vollum Institute and a Howard Hughes Medical Institute investigator. “It’s definitely going to make translational research possible that was not possible before.”

These structures illuminate the conformational rearrangements that underlie P2X receptor gating and provide a foundation for the development of new pharmacological agents for the treatment of conditions including high blood pressure and early formation of blood clots.

Additional authors include Wei Lu, Ph.D., of the Vollum Institute; Wout Oosterheert, now with Utrecht University in The Netherlands; and Mrinal Shekhar and Emad Tajkhorshid, Ph.D., of the Center for Biophysics and Quantitative Biology and Beckman Institute for Advanced Science and Technology, respectively, at the University of Illinois at Urbana-Champaign.

This research was supported by the National Institute of General Medical Sciences (5F32GM108391 to S.E.M and R01GM100400 to E.G.).