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	Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.
ジャーナル・号・ページ	Sci Adv, Vol. 9, Issue 48, Page eadk6191, Year 2023
掲載日	2023年12月1日
著者	Marta Sanz Murillo / Amalia Villagran Suarez / Verena Dederer / Deep Chatterjee / Jaime Alegrio Louro / Stefan Knapp / Sebastian Mathea / Andres E Leschziner /
PubMed 要旨	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 ...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.
リンク	Sci Adv / PubMed:38039358 / PubMed Central
手法	EM (単粒子)
解像度	2.7 - 3.9 Å
構造データ	41709 8txz EMDB-41709, PDB-8txz: Structure of C-terminal LRRK2 bound to MLi-2 手法: EM (単粒子) / 解像度: 3.05 Å 41728 8tyq EMDB-41728, PDB-8tyq: Structure of the C-terminal half of LRRK2 bound to GZD-824 (G2019S mutant) 手法: EM (単粒子) / 解像度: 2.99 Å 41753 8tzb EMDB-41753, PDB-8tzb: Structure of the C-terminal half of LRRK2 bound to GZD-824 (I2020T mutant) 手法: EM (単粒子) / 解像度: 3.1 Å 41754 8tzc EMDB-41754, PDB-8tzc: Structure of C-terminal LRRK2 bound to MLi-2 (G2019S mutant) 手法: EM (単粒子) / 解像度: 2.7 Å 41756 8tze EMDB-41756, PDB-8tze: Structure of C-terminal half of LRRK2 bound to GZD-824 手法: EM (単粒子) / 解像度: 2.9 Å 41757 8tzf EMDB-41757, PDB-8tzf: Structure of full length LRRK2 bound to GZD-824 (I2020T mutant) 手法: EM (単粒子) / 解像度: 3.4 Å 41758 8tzg EMDB-41758, PDB-8tzg: Structure of C-terminal LRRK2 bound to MLi-2 (I2020T mutant) 手法: EM (単粒子) / 解像度: 2.7 Å 41759 8tzh EMDB-41759, PDB-8tzh: Structure of full-length LRRK2 bound to MLi-2 (I2020T mutant) 手法: EM (単粒子) / 解像度: 3.9 Å EMDB-41794: Structure of C-terminal half of LRRK2 (I2020T mutant) bound to GZD-824, Kinase-WD40 手法: EM (単粒子) / 解像度: 3.06 Å EMDB-41795: Structure of C-terminal half of LRRK2 (I2020T mutant) bound to GZD-824, ROC-COR domain 手法: EM (単粒子) / 解像度: 3.63 Å EMDB-41797: Structure of C-terminal half of LRRK2 (G2019S mutant) bound to GZD-824, ROC-COR domain 手法: EM (単粒子) / 解像度: 3.5 Å EMDB-41798: Structure of C-terminal half of LRRK2 bound tp GZFD-824 (G2019S mutant) 手法: EM (単粒子) / 解像度: 3.1 Å EMDB-41799: Structure of C-terminal half of LRRK2 bound to GZD-824 (G2019S mutant), Kinase-WD40 手法: EM (単粒子) / 解像度: 2.99 Å EMDB-41802: Structure of C-terminal half of LRRK2 bound to GZD-824 (I2020T mutant) 手法: EM (単粒子) / 解像度: 3.22 Å
化合物	ChemComp-A1N: (2~{R},6~{S})-2,6-dimethyl-4-[6-[5-(1-methylcyclopropyl)oxy-1~{H}-indazol-3-yl]pyrimidin-4-yl]morpholine / 5-(1-メチルシクロプロパン-1-イルオキシ)-3-[6-(2β,6β-ジメチルモルホリン-4-イル)ピリミジン-4(以下略) ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP / GDP, エネルギー貯蔵分子YM ChemComp-HOH: WATER 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-MG*: Unknown entry / マグネシウムジカチオン
由来	homo sapiens (ヒト) synthetic construct (人工物)
キーワード	PROTEIN BINDING / GTPase / kinase / inhibitors / Kinase inhibitors / GTPases