Author

Lawrence Y. Zhu

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Open access Jun 2026

The structural basis for LRRK2’s activation and autoinhibition

Mutations in Leucine-Rich Repeat Kinase 2 (LRRK2) are the second most common cause of autosomal-dominant Parkinson’s disease (PD), and increased LRRK2 kinase activity is also observed in idiopathic PD, making LRRK2 a major actionable therapeutic target. LRRK2 is a 286-kDa multidomain enzyme containing a Ras-like GTPase...

Amalia Villagran Suarez, Kathryn S. Hatch, Tatyana Bodrug et al. · bioRxiv · 1 citation

Open access Sep 2026

Chemical Genetic Targeting of the LRRK2 GTPase Domain

Genetic variants throughout the multi-domain protein leucine-rich repeat kinase 2 (LRRK2) gene are the most common cause of autosomal dominant Parkinson’s disease, and the most prevalent Parkinson’s-associated LRRK2 variants enhance kinase activity. Hence, the kinase domain has been extensively targeted for therapeutic...

Rachel E. Prorok, Lawrence Y. Zhu, Vickie Bowcut et al. · bioRxiv · 0 citations

Open access Aug 2026

The structural basis for LRRK2's activation and autoinhibition.

A unified framework for understanding LRRK2 regulation with broad therapeutic implications is provided, showing that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition.

Amalia Villagran Suarez, Kathryn S. Hatch, Tatyana Bodrug et al. · Cell · 0 citations