Parkinson’s-Linked Gene Product May Be Druggable, Structural Study Finds

Parkinson’s

Opposites often attract in the world of romance, but they also attract inside the human body when receptors located on or in cells bind to other molecules, including medications. In fact, some cellular receptors have special “pockets” that only bind molecules with a specific shape to fit them—kind of like finding the right hand to fit a glove.

A new Scripps Research study finds that receptors for a Parkinson’s-associated gene product have a pocket needed to bind to other molecules, opening the ability to more accurately probe its role in disease, and possibly develop a new class of therapies, according to research published recently in CellPress. The gene, called Nurr1, may enable certain neurons to create the neurotransmitter dopamine, in addition to helping them survive various toxic stressors. Loss of dopamine is a cause of the tremors and rigidity associated with Parkinson’s.

This research is the first to identify that Nurr1 receptors, which were previously thought to lack binding pockets for ligands, or binding molecules, actually do have pockets that make them potentially druggable, says Douglas Kojetin, PhD, an Associate Professor in the Department of Integrative and Structural Computational Biology and the Department of Molecular Medicine at Scripps Research.

“Our study showed that the pocket can actually open and close, and when an unsaturated fatty acid binds, such as DHA, it can actually induce a further opening of the pocket,” Kojetin says. “We found that there are natural ligands that bind to the Nurr1 receptor, and that Nurr1 binds natural and synthetic drug-like ligands that way other receptors do.”

To get a better idea of how the Nurr1 receptor responds to different binding molecules, Kojetin and his colleagues used several highly sophisticated technologies including nuclear magnetic resonance spectroscopy, which, similar to MRI instruments, uses high-field magnets to study the receptor on the atomic level, along with mass spectrometry and computer simulations to help them better observe the Nurr1 receptor’s behavior when exposed to different solutions. They compared “before-and-after” images of the receptor and found the Nurr1 receptor changed shapes in altered environments.

“These results may surprise some people because many people in the pharmaceutical industry previously thought that Nurr1 could not bind a ligand in the same way other receptors do, but our study is proof-of-concept that the Nurr1 receptor binds ligands,” Kojetin says. “The next step is to determine if these Nurr1-binding molecules can be used to target Parkinson’s disease.”

Additional authors of the study, “Defining a Canonical Ligand-Binding Pocket in the Orphan Nuclear Receptor Nurr1,” were Ian Mitchelle S. De Vera, Paola Muñoz-Tello, Jinsai Shang, Travis Hughes, Pankaj Kumar Giri,  Patrick Griffin, Edna Matta-Camacho,Jie Zheng, Venkatasubramanian Dharmarjan, and David Marciano of Scripps Research, along with Mark Rance from the Department of Molecular Genetics at the University of Cincinnati.

This research was made possible by the National Institutes of Health (NIH) grantsR01GM114420 and K99DK103116; the National Science Foundation (NSF) funding to the Summer Undergraduate Research Fellows (SURF) program at Scripps Research in Florida (1659594); and the Academic Year Research Internship for Undergraduates (AYRIU) program at Scripps Research;A portion of this work was performed at the National High Magnetic Field Laboratory (NHMFL/MagLab), which is supported by the National Science Foundation (NSF; DMR-1157490).