Researchers at Weill Cornell Medicine have revealed how LRRK2, a protein strongly associated with Parkinson’s disease, switches between inactive and active states. The study, published in Cell, provides the most detailed structural explanation yet of how LRRK2 mutations can drive excessive protein activity. Because abnormal LRRK2 signaling is one of the most common genetic contributors to Parkinson’s—and can also be elevated in people without inherited LRRK2 mutations—the findings could help guide the development of more precise treatments for the disease.
LRRK2 is a large molecular machine involved in organizing materials inside cells. It is found in the brain as well as in immune cells, the lungs and the kidneys, where it performs functions that are not yet fully understood. The protein contains seven distinct domains, including regions that bind other cellular components and two enzymatic units. One of these enzymes is a kinase, which modifies target proteins by attaching phosphate groups to them. Excessive phosphorylation by LRRK2 is associated with Parkinson’s-related cellular dysfunction.
A second enzymatic region acts as a molecular switch by binding either GTP or GDP. In many cellular signaling proteins, GTP binding corresponds to an active state, while conversion of GTP to GDP helps return the protein to an inactive state. LRRK2, however, is controlled by a more intricate relationship between its switch and kinase domains. The Weill Cornell team set out to determine how these regions communicate and how their interaction controls access to the kinase’s active site.
Using cryo-electron microscopy alongside biochemical experiments, the researchers captured LRRK2 in a broad collection of structural states. They examined 16 different configurations, including molecules bound to GTP, molecules bound to GDP and molecules carrying neither nucleotide. These snapshots allowed the investigators to reconstruct the protein’s movements as it transitions between inactive and active forms, much like assembling a molecular film from individual frames.
The structures showed that GDP plays a central role in restraining LRRK2. When GDP is bound, LRRK2 adopts a compact conformation in which several domains fold toward one another and obstruct the kinase active site. This arrangement prevents the kinase from effectively contacting its protein targets. When GDP is released, the molecule undergoes a substantial rearrangement. Its domains move apart, exposing the active site and allowing the kinase to phosphorylate other proteins. Binding of GTP can then help stabilize this active configuration.
“This work provides a platform for identifying molecules that promote the formation of one configuration or the other,” said Dr. Samara Reck-Peterson, chair and professor of biochemistry and biophysics at Weill Cornell Medicine and an investigator at the Howard Hughes Medical Institute. Such compounds could allow researchers to control LRRK2 by influencing its overall shape rather than simply blocking the catalytic site. That approach may be especially valuable because LRRK2 carries out normal functions in several organs, making broad suppression potentially undesirable.
The structural data also clarified how Parkinson’s-associated mutations activate LRRK2 through different mechanisms. One well-known mutation occurs directly within the kinase domain and can increase the enzyme’s catalytic performance. Other mutations are located far from the kinase active site, including near the GTP-GDP switching machinery. Rather than making the kinase intrinsically faster, these distant mutations appear to increase the amount of time LRRK2 spends in its active conformation.
That distinction could have important consequences for treatment design. A drug that blocks the kinase’s catalytic pocket may work against mutations that directly enhance enzymatic activity, but it may not fully address mutations that alter the protein’s switching behavior. In the latter cases, an allosteric drug—one that binds at a regulatory site away from the active center—could potentially shift LRRK2 toward its inactive architecture. “Such allosteric drugs may offer greater precision and fewer side effects than conventional kinase inhibitors,” said Dr. Andres Leschziner, professor of biochemistry and biophysics at Weill Cornell and co-lead investigator.
The findings arrive as LRRK2 inhibitors and related compounds move through clinical testing, with at least four trials underway. The new structural blueprint could help medicinal chemists design therapies that selectively stabilize the off state or prevent disease-linked mutations from prolonging the on state. The study, led by Weill Cornell researchers with collaborators at the University of California, San Francisco, and Goethe University in Frankfurt, was co-first-authored by graduate students Amalia Villagran Suarez and Kathryn Hatch. By showing precisely how LRRK2’s domains cooperate to control its activity, the work brings researchers closer to mutation-specific strategies for slowing Parkinson’s disease while preserving the protein’s normal biological roles.
Subject of Research: LRRK2 protein activation and autoinhibition in Parkinson’s disease
Article Title: The structural basis for LRRK2’s activation and autoinhibition
News Publication Date: 10-Aug-2026
Web References: https://doi.org/10.1016/j.cell.2026.07.027; https://vivo.weill.cornell.edu/display/cwid-slr4003; https://vivo.weill.cornell.edu/display/cwid-ale4009
References: Cell, DOI: 10.1016/j.cell.2026.07.027
Image Credits: Weill Cornell Medicine
Keywords: Parkinson’s disease, LRRK2, protein structure, cryo-electron microscopy, kinase activity, GTP-GDP switch, molecular biology, allosteric drugs, neurodegenerative disease, biomedical research
