9OXH

Full length LRRK2 bound to G10 DARPin

Summary for 9OXH

• Entry DOI: 10.2210/pdb9oxh/pdb
• EMDB information: 70981
• Descriptor: Leucine-rich repeat serine/threonine-protein kinase 2, DARPin G10, MAGNESIUM ION, ... (4 entities in total)
• Functional Keywords: complex, kinase, gtpases, structural protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 2
• Total formula weight: 306881.32

Authors

Villagran, A.V.,Bodrug, T.,Leschziner, A. (deposition date: 2025-06-03, release date: 2026-08-12, Last modification date: 2026-08-19)

Primary citation

Villagran Suarez, A.,Hatch, K.S.,Bodrug, T.,Gai, W.,Surridge, K.J.,Moussikhina, E.,Nguyen, K.H.V.,Sanz-Murillo, M.,Callahan, R.,Xiong, E.,Ramos, D.,Zhu, L.,Dederer, V.,Mathea, S.,Iwasa, J.,Knapp, S.,Shokat, K.M.,Reck-Peterson, S.L.,Leschziner, A.E.
The structural basis for LRRK2's activation and autoinhibition.
Cell, 2026

PubMed Abstract: 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 (ROC) and a kinase domain. Using cryo-electron microscopy (cryo-EM), biochemical reconstitution, and cell-based assays, we show that the ROC GTPase governs switching between autoinhibited and active states: GTP binding promotes activation, whereas GDP binding enforces autoinhibition. Two common PD-linked mutations, G2019S and R1441C/G/H, activate LRRK2 through distinct structural mechanisms, revealing genotype-specific routes to dysregulation. These findings provide a unified framework for understanding LRRK2 regulation with broad therapeutic implications. Stabilizing the guanosine diphosphate (GDP)-bound state may inhibit LRRK2 by maintaining autoinhibition, whereas promoting the GTP-bound state could be advantageous in specific cellular contexts, such as the lung, where increased LRRK2 kinase activity may play protective or regulatory roles.

PubMed: 42575089
DOI: 10.1016/j.cell.2026.07.027

Experimental method

ELECTRON MICROSCOPY (3.15 Å)