8TZC

Structure of C-terminal LRRK2 bound to MLi-2 (G2019S mutant)

8TZC の概要

• エントリーDOI: 10.2210/pdb8tzc/pdb
• 関連するPDBエントリー: 8TXZ
• EMDBエントリー: 41754
• 分子名称: Leucine-rich repeat serine/threonine-protein kinase 2, E11 DARPin, (2~{R},6~{S})-2,6-dimethyl-4-[6-[5-(1-methylcyclopropyl)oxy-1~{H}-indazol-3-yl]pyrimidin-4-yl]morpholine, ... (5 entities in total)
• 機能のキーワード: gtpase, kinase, inhibitors, protein binding
• 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: 156794.37

構造登録者

Sanz-Murillo, M.,Villagran-Suarez, A.,Alegrio-Louro, J.,Leschziner, A. (登録日: 2023-08-26, 公開日: 2023-12-06, 最終更新日: 2024-10-23)

主引用文献

Sanz Murillo, M.,Villagran Suarez, A.,Dederer, V.,Chatterjee, D.,Alegrio Louro, J.,Knapp, S.,Mathea, S.,Leschziner, A.E.
Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.
Sci Adv, 9:eadk6191-eadk6191, 2023

PubMed Abstract: Mutations in leucine-rich repeat kinase 2 (LRRK2) are a common cause of familial Parkinson's disease (PD) and a risk factor for the sporadic form. Increased kinase activity was shown in patients with both familial and sporadic PD, making LRRK2 kinase inhibitors a major focus of drug development efforts. Although much progress has been made in understanding the structural biology of LRRK2, there are no available structures of LRRK2 inhibitor complexes. To this end, we solved cryo-electron microscopy structures of LRRK2, wild-type and PD-linked mutants, bound to the LRRK2-specific type I inhibitor MLi-2 and the broad-spectrum type II inhibitor GZD-824. Our structures revealed an active-like LRRK2 kinase in the type I inhibitor complex, and an inactive DYG-out in the type II inhibitor complex. Our structural analysis also showed how inhibitor-induced conformational changes in LRRK2 are affected by its autoinhibitory N-terminal repeats. The structures provide a template for the rational development of LRRK2 kinase inhibitors covering both canonical inhibitor binding modes.

PubMed: 38039358
DOI: 10.1126/sciadv.adk6191

実験手法

ELECTRON MICROSCOPY (2.7 Å)