Study findings ‘lay foundation’ for targeted therapies in Parkinson’s
Researchers say new USP30 inhibitor could have strong, lasting effects
A small molecule called NK036 — which inhibits USP30, an enzyme that counters the removal of damaged mitochondria from nerve cells in Parkinson’s disease — fits tightly into its target, suggesting it may have a strong and lasting effect as a treatment for the neurological condition, a new study found.
Developed in the lab of Malte Gersch, PhD, at the Max Planck Institute for Molecular Physiology in Germany, NK036 sits deeply in the enzyme, forming stable connections that let researchers see how exactly USP30 inhibitors interact with their target.
According to the researchers, these findings suggest that advancing NK036 could ultimately lead to new targeted therapies for Parkinson’s.
“Elucidating the mechanism of action of this potential Parkinson’s drug will not only help to further develop it, but also lay the foundation for designing new drug molecules against USP30,” Gersch, a chemical biologist and the research group leader, said in an institute news story.
The study, “Chimeric deubiquitinase engineering reveals structural basis for specific inhibition of the mitophagy regulator USP30,” was published in the journal Nature Structural & Molecular Biology.
Small molecule NK036 could lead to targeted Parkinson’s therapies
A process known as mitophagy removes damaged mitochondria — the small compartments responsible for producing energy in cells — by tagging them with a protein called ubiquitin. USP30, present on mitochondria, counters mitophagy by removing the ubiquitin tags. This can lead to a buildup of damaged mitochondria, which may drive the death of dopamine-producing nerve cells. Dopamine is involved in motor control, and its loss causes symptoms of Parkinson’s.
While inhibiting USP30 may increase mitophagy and prevent the loss of dopamine-producing nerve cells to slow the progression of Parkinson’s, exactly how small molecules specifically block this enzyme has remained unclear.
“One problem with the human protein USP30 is that it is difficult to ‘photograph’ — its molecular structure is difficult to elucidate,” Gersch said, noting that “USP30 is very flexible — you could say it wriggles around in front of the camera.”
But, Gersch noted, “if you want to see how the inhibitor binds to the protein, you can use X-rays to produce a so-called ‘diffraction pattern’ of the two partners in a crystal.”
Our work opens new avenues for the structure-based drug design of [inhibitors of USP30 and other similar enzymes] and enables the rational optimization of therapeutics targeting neurodegeneration.
To counter USP30’s flexibility, Gersch’s team used chimeric protein engineering, which means they slightly changed the enzyme to make it less mobile and easier to study, without changing its key parts.
X-rays were then used to see how NK036 fits into USP30 when they are bound to each other.
The scientists found that NK036 binds to a hidden pocket in USP30, and at the same time to a hotspot that is also accessible to other inhibitors. The hidden pocket only opened when the enzyme changed shape after interacting with the inhibitor, the team noted. Thus, targeting this shape-shifting region could help design better inhibitors for USP30 and other similar enzymes, per the researchers.
The team characterized their findings as “exciting.”
“Our work opens new avenues for the structure-based drug design of [inhibitors of USP30 and other similar enzymes] and enables the rational optimization of therapeutics targeting neurodegeneration,” the researchers wrote.
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