Adam Oken, B.A., a graduate student in the Mansoor lab, points to a cryo-EM map (blue) and its corresponding model (mostly yellow and other colors). The cryo-EM map is generated after processing data obtained from the “advanced imaging techniques” and it directly corresponds to the position of atoms in 3D space. The assembly of thousands of atoms forms the protein structure or “model.” Credit: OHSU/Christine Torres Hicks

In 2019, Steven Mansoor, M.D., Ph.D., a physician–scientist at Oregon Health & Science University, and his research team made a groundbreaking discovery: They determined the first complete structure of a protein linked to various health issues ranging from cancer to nerve pain to brain disorders.

The protein they studied is the P2X7 receptor, an ion channel that is found throughout the body. P2X7 is unique: once it’s activated, it remains open for a long time, letting ions—molecules with a net positive or negative electrical charge—readily flow in and out of the cell.

This prolonged ion exchange can trigger inflammation and eventually lead to cell death, which might explain why it’s connected to so many health problems like inflammation, plaque in arteries, cancer spread and neurological issues.

In a new paper published today in Science Advances, Mansoor and Adam Oken, B.A., a graduate student in the Mansoor lab, used advanced imaging techniques to look at the structure of the P2X7 receptor once it’s bound to five known antagonists and a new one they discovered. Antagonists are molecules that bind to the receptor and prevent it from activating, effectively blocking receptor function.

Their findings reveal how these antagonists interact with the receptor to block its function and show that there are at least three types of blockers: shallow, deep and starfish. Starfish blockers, exemplified by the newly identified ligand named methyl blue, exhibit unique characteristics that could pave the way for developing more effective treatments for P2X7-related conditions.

“There are seven different subtypes, P2X1 through P2X7, that each play important roles in various aspects of cellular physiology ranging from processes in the central nervous system to aspects of the cardiovascular system and the immune system,” said Mansoor, an assistant professor of medicine (cardiovascular medicine) and chemical and physiology and biochemistry in the OHSU School of Medicine and Knight Cardiovascular Institute.

“We are really interested in understanding how the seven P2X receptor subtypes differ from each other at a molecular level. This is important because if you wanted to design a drug that blocks the activation of P2X7, you do not want to affect the function of other receptors.”

Steven Mansoor, M.D., Ph.D., and his research team at Oregon Health & Science University have discovered a way to turn off a receptor linked to many inflammatory diseases. They used advanced imaging techniques to look at the structure of the P2X7 receptor once it’s bound to five known antagonists and a new one they discovered. Credit: OHSU/Christine Torres Hicks

Turning P2X7 on and off

A Mansoor lab paper published in August in Nature Communications was complementary to the current study. Oken, first author on both manuscripts, used advanced imaging techniques to look at the structure of the P2X7 receptor bound to a strong activator called BzATP. They found that three specific parts of the receptor play a key role in its strong response to BzATP—shedding light on how P2X receptors turn on.

Now, in the Science Advances paper, the researchers take their findings further by figuring out not only how to turn the receptor on, but also how to turn it off. The aim of the Mansoor lab is to develop molecules that can precisely target and control the receptor’s function.

“When P2X7 is turned on, it signals for the release of unsafe molecules that trigger inflammation,” Oken said. “Our goal is to understand how to turn off P2X7 activity by designing ligands that bind very tightly to turn off harmful P2X7 signaling. Eventually, this can lead to new therapeutics that have the potential to treat heart disease, cancer and other inflammatory diseases.”

In 2022, Mansoor started to develop better drugs by understanding how P2X receptors work at the molecular level. This newest study continues his quest for drug development to block activation of these receptors involved in inflammatory diseases.