8U7H

Cryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915

8U7H の概要

• エントリーDOI: 10.2210/pdb8u7h/pdb
• EMDBエントリー: 41982
• 分子名称: non-specific serine/threonine protein kinase, GUANOSINE-5'-DIPHOSPHATE, [4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-2-fluoranyl-5-methoxy-phenyl]-morpholin-4-yl-methanone (3 entities in total)
• 機能のキーワード: cryo-em, parkinson's disease, kinase, lrrk2, type i inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 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: 137730.07

構造登録者

Zhu, H.,Sun, J. (登録日: 2023-09-15, 公開日: 2024-01-31)

主引用文献

Zhu, H.,Hixson, P.,Ma, W.,Sun, J.
Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.
Cell Discov, 10:10-10, 2024

PubMed Abstract: LRRK2 is one of the most promising drug targets for Parkinson's disease. Though type I kinase inhibitors of LRRK2 are under clinical trials, alternative strategies like type II inhibitors are being actively pursued due to the potential undesired effects of type I inhibitors. Currently, a robust method for LRRK2-inhibitor structure determination to guide structure-based drug discovery is lacking, and inhibition mechanisms of available compounds are also unclear. Here we present near-atomic-resolution structures of LRRK2 with type I (LRRK2-IN-1 and GNE-7915) and type II (rebastinib, ponatinib, and GZD-824) inhibitors, uncovering the structural basis of LRRK2 inhibition and conformational plasticity of the kinase domain with molecular dynamics (MD) simulations. Type I and II inhibitors bind to LRRK2 in active-like and inactive conformations, so LRRK2-inhibitor complexes further reveal general structural features associated with LRRK2 activation. Our study provides atomic details of LRRK2-inhibitor interactions and a framework for understanding LRRK2 activation and for rational drug design.

PubMed: 38263358
DOI: 10.1038/s41421-023-00639-8

実験手法

ELECTRON MICROSCOPY (3.8 Å)