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."
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 received the NIH Director's New Innovator Award for his work 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.
OHSU research assistants in Mansoor's lab, Ismayn Ditter, B.A., Nicolas Lisi, B.A., and Ipsita Krishnamurthy, B.A., as well as a research associate Michael Godsey, Ph.D., contributed to this study.
Mansoor is a 2020 recipient of an OHSU Faculty Excellence and Innovation Award.
This study was supported by the National Institutes of Health grant U24GM129547 and performed at the PNCC at OHSU and accessed through EMSL (grid.436923.9), a DOE Office of Science User Facility sponsored by the Office of Biological and Environmental Research. This work was supported by the National Institute of Health (grants R00HL138129 and DP2GM149551 to S.E.M.) and the American Heart Association (grant 24PRE1195450 to A.C.O.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or AHA.
