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Study in Nature Reveals New Molecular Insight

Researchers at OHSU open new avenue for developing medications
P2X molecular receptor
P2X molecular receptor

New research reveals for the first time the atomic structures of a key molecular receptor in the brain, which opens the door for developing medications that could block activation of these receptors to address a variety of conditions, ranging from pain to high blood pressure to early formation of blood clots. The study, which culminates 3 ½ years of research, is being published online today in the journal Nature

The research focuses on one type of a family of ligand-gated ion channels known as P2X receptors, a protein molecule that activates a cell when it senses chemical signals from the environment. This particular receptor senses ATP, an organic compound that is the energy currency of the human body. Once this compound binds to the receptor, it causes a change in the receptor’s structure to open a pore for ions such as sodium and calcium to flow into the cell. Yet the P2X receptor pore closes quickly, meaning it becomes “desensitized,” even in the continued presence of ATP. By understanding how the receptor changes its structure to open and close its pore, scientists may now be able to develop new pharmacological agents capable of binding to the receptor and keeping the channel closed. 

“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 the Knight Cardiovascular Institute and Vollum Institute at Oregon Health & Science University. 

“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.”

In addition to Mansoor and Gouaux, 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. 

The simulations were supported by the National Institutes of General Medical Sciences (U54-GM087519 and P41-GM104601 to E.T.) and computationally through XSEDE (TG-MCA06N060 to E.T.). E.G. is an investigator with the Howard Hughes Medical Institute. This research was supported by the National Institute of General Medical Sciences (5F32GM108391 to S.E.M and R01GM100400 to E.G.).


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