8FO2

Cryo-EM structure of Rab29-LRRK2 complex in the LRRK2 monomer state

8FO2 の概要

• エントリーDOI: 10.2210/pdb8fo2/pdb
• EMDBエントリー: 29339
• 分子名称: Ras-related protein Rab-7L1, Leucine-rich repeat serine/threonine-protein kinase 2, MAGNESIUM ION, ... (6 entities in total)
• 機能のキーワード: cryo-em, parkinson's disease, kinase, lrrk2, rab gtpases, activation, hydrolase
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 308163.61

構造登録者

Zhu, H.,Sun, J. (登録日: 2022-12-29, 公開日: 2024-01-03)

主引用文献

Zhu, H.,Tonelli, F.,Turk, M.,Prescott, A.,Alessi, D.R.,Sun, J.
Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2.
Science, 382:1404-1411, 2023

PubMed Abstract: Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment.

PubMed: 38127736
DOI: 10.1126/science.adi9926

実験手法

ELECTRON MICROSCOPY (4.13 Å)