9DMI

Structure of the C-terminal half of LRRK2 bound to RN277 (Type-II inhibitor)

これはPDB形式変換不可エントリーです。

9DMI の概要

• エントリーDOI: 10.2210/pdb9dmi/pdb
• EMDBエントリー: 47006
• 分子名称: Leucine-rich repeat serine/threonine-protein kinase 2, E11 DARPin, N-[3-tert-butyl-1-(4-methylphenyl)-1H-pyrazol-5-yl]-N'-{(3M)-3-[2-chloro-4-(morpholin-4-yl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl]phenyl}urea (3 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: 156526.79

構造登録者

Sanz-Murillo, M.,Leschziner, A. (登録日: 2024-09-13, 公開日: 2025-06-18)

主引用文献

Raig, N.D.,Surridge, K.J.,Sanz-Murillo, M.,Dederer, V.,Kramer, A.,Schwalm, M.P.,Lattal, N.M.,Elson, L.,Chatterjee, D.,Mathea, S.,Hanke, T.,Leschziner, A.E.,Reck-Peterson, S.L.,Knapp, S.
Type II kinase inhibitors that target Parkinson's disease-associated LRRK2.
Sci Adv, 11:eadt2050-eadt2050, 2025

PubMed Abstract: Increased kinase activity of leucine-rich repeat kinase 2 (LRRK2) is associated with Parkinson's disease (PD). Numerous LRRK2-selective type I kinase inhibitors have been developed, and some have entered clinical trials. Here, to our knowledge, we present the first type II kinase inhibitors that target LRRK2. Targeting the inactive conformation of LRRK2 is functionally distinct from targeting the active-like conformation using type I inhibitors. We designed these inhibitors with a combinatorial chemistry approach fusing selective LRRK2 type I and promiscuous type II inhibitors using iterative cycles of synthesis supported by structural biology and activity testing. Our lead compounds are selective and potent toward both LRRK2 and LRRK1, a close relative of LRRK2. Through cellular assays, cryo-electron microscopy structural analysis, and in vitro motility assays, we show that our inhibitors stabilize the open, inactive LRRK2 kinase conformation. These new conformation-specific compounds will be invaluable as tools to study LRRK2's function and regulation and expand the potential therapeutic options for PD.

PubMed: 40465731
DOI: 10.1126/sciadv.adt2050

実験手法

ELECTRON MICROSCOPY (3.35 Å)