Study reveals structure of potential drug target in neurological conditions

By Sally Robertson, B.Sc.Sep 25 2018Reviewed by James Ives, M.Psych. (Editor)

Researchers at Van Andel Research Institute (VARI) have revealed the atomic-level structure of a protein that could serve as a promising new drug target for the treatment of neurological conditions such as bipolar disorder and Alzheimer’s disease.

TRPM2 is absolutely critical for healthy function but, until today, we were missing key insights into its structure and mechanism of action. It is our hope that these findings will act as a schematic for designing better and desperately needed medications for a host of neurological conditions."

Co-senior author of the study, Juan Du.

TRPM2 is involved in regulating body temperature, immune responses and apoptosis (programmed cell death). The protein is activated by various stimuli including oxidative stress, which is associated with a range of neurological conditions.

It is a member of the TRP superfamily, which is a group of proteins involved in how the body responds to sensory stimuli such as temperature, taste and pain. Also referred to as ion channels, these proteins are located in the cell membrane where they serve as “gatekeepers” for chemical signals entering and exiting the cell.

As reported in the journal Nature, the new images produced at VARI show the protein is bell-like in structure and has a transmembrane domain region on its shoulder and an expanded NUDT9-H domain on its lip. The images also revealed a new binding site for a messenger molecule called ADPT that is associated with oxidative stress. This finding contradicts previous understanding that it is the NUDT9-H domain of TRPM2 that ADPR binds to.

These new insights could be key to helping researchers design new drugs for the treatment of temperature-related diseases and the prevention of neuronal death in neurodegenerative diseases.

"Although we have known for some time that TRPM2 is a vital component of many biological processes and a possible drug target, we didn't know exactly what it looked like or how it worked. Today's findings change that and go a long way toward a more comprehensive understanding of these incredibly important molecules," says co-senior author Wei Lü.