9OM2

Full-length LRRK2 autoinhibited

9OM2 の概要

• エントリーDOI: 10.2210/pdb9om2/pdb
• EMDBエントリー: 70604
• 分子名称: Leucine-rich repeat serine/threonine-protein kinase 2, GUANOSINE-5'-DIPHOSPHATE (2 entities in total)
• 機能のキーワード: kinase, gtpase, transferase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 286905.98

構造登録者

Villagran-Suarez, A.C.,Bodrug, T. (登録日: 2025-05-13, 公開日: 2026-08-12, 最終更新日: 2026-08-19)

主引用文献

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

実験手法

ELECTRON MICROSCOPY (3.31 Å)