EMDB/PDB/SASBDBから引用されている文献のデータベース

キーワード
構造解析手法	All X線回折 NMR 電子顕微鏡小角散乱中性子線回折線維回折粉末回折赤外分光 EPR FRET 理論モデルハイブリッド
著者・登録者
ジャーナル
IF	>30 >20 >10 >5 all

タイトル	Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.
ジャーナル・号・ページ	Cell Discov, Vol. 10, Issue 1, Page 10, Year 2024
掲載日	2024年1月23日
著者	Hanwen Zhu / Patricia Hixson / Wen Ma / Ji Sun /
PubMed 要旨	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 ...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.
リンク	Cell Discov / PubMed:38263358 / PubMed Central
手法	EM (単粒子)
解像度	3.4 - 3.8 Å
構造データ	29340 8fo7 EMDB-29340, PDB-8fo7: Cryo-EM structure of LRRK2 bound to type I inhibitor LRRK2-IN-1 手法: EM (単粒子) / 解像度: 3.52 Å 41982 8u7h EMDB-41982, PDB-8u7h: Cryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915 手法: EM (単粒子) / 解像度: 3.8 Å 41985 8u7l EMDB-41985, PDB-8u7l: Cryo-EM structure of LRRK2 bound to type II inhibitor GZD824 手法: EM (単粒子) / 解像度: 3.6 Å 42019 8u8a EMDB-42019, PDB-8u8a: Cryo-EM structure of LRRK2 bound to type II inhibitor ponatinib 手法: EM (単粒子) / 解像度: 3.4 Å 42020 8u8b EMDB-42020, PDB-8u8b: Cryo-EM structure of LRRK2 bound to type II inhibitor rebastinib 手法: EM (単粒子) / 解像度: 3.7 Å
化合物	ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP / GDP, エネルギー貯蔵分子YM ChemComp-4K4: 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one / LRRK2-IN-1 ChemComp-A0T: [4-[[4-(ethylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]-2-fluoranyl-5-methoxy-phenyl]-morpholin-4-yl-methanone ChemComp-T3X: 4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}-3-[(1H-pyrazolo[3,4-b]pyridin-5-yl)ethynyl]benzamide ChemComp-0LI: 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl}benzam / ポナチニブ / 薬剤YM ChemComp-919: 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide / レバスチニブ
由来	homo sapiens (ヒト)
キーワード	HYDROLASE/HYDROLASE INHIBITOR / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / type I inhibitor / LRRK2-IN-1 / HYDROLASE-HYDROLASE INHIBITOR complex / HYDROLASE / type II inhibitor