The structural basis for LRRK2's activation and autoinhibition.

GTP binding to LRRK2's ROC domain triggers activation, while GDP binding enforces autoinhibition, revealing distinct structural mechanisms for PD-linked mutations G2019S and R1441C/G/H.

• Why it matters: Understanding how LRRK2 switches between active and inactive states is crucial because mutations that dysregulate its activity are major causes of Parkinson's disease, and targeting this regulation offers therapeutic potential.
• What they did: Using cryo-EM, biochemical reconstitution, and cell assays, the study examined the structural basis of LRRK2 regulation, identifying how GTP and GDP binding control its activity and how mutations alter these mechanisms.
• The result: The findings suggest stabilizing the GDP-bound state could inhibit LRRK2, while promoting GTP binding might be beneficial in certain tissues, advancing targeted therapies for PD and related conditions.