Database of articles cited by EMDB/PDB/SASBDB data

Keywords
Structure methods	All X-ray diffraction NMR electron microscopy small angle scattering neutron diffraction fiber diffraction powder diffraction infrared spectroscopy EPR fluorescence transfer theoretical model Hybrid
Author
Journal
IF	>30 >20 >10 >5 all

Title	Pharmacology of LRRK2 with type I and II kinase inhibitors revealed by cryo-EM.
Journal, issue, pages	Cell Discov, Vol. 10, Issue 1, Page 10, Year 2024
Publish date	Jan 23, 2024
Authors	Hanwen Zhu / Patricia Hixson / Wen Ma / Ji Sun /
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 ...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.
External links	Cell Discov / PubMed:38263358 / PubMed Central
Methods	EM (single particle)
Resolution	3.4 - 3.8 Å
Structure data	29340 8fo7 EMDB-29340, PDB-8fo7: Cryo-EM structure of LRRK2 bound to type I inhibitor LRRK2-IN-1 Method: EM (single particle) / Resolution: 3.52 Å 41982 8u7h EMDB-41982, PDB-8u7h: Cryo-EM structure of LRRK2 bound to type I inhibitor GNE-7915 Method: EM (single particle) / Resolution: 3.8 Å 41985 8u7l EMDB-41985, PDB-8u7l: Cryo-EM structure of LRRK2 bound to type II inhibitor GZD824 Method: EM (single particle) / Resolution: 3.6 Å 42019 8u8a EMDB-42019, PDB-8u8a: Cryo-EM structure of LRRK2 bound to type II inhibitor ponatinib Method: EM (single particle) / Resolution: 3.4 Å 42020 8u8b EMDB-42020, PDB-8u8b: Cryo-EM structure of LRRK2 bound to type II inhibitor rebastinib Method: EM (single particle) / Resolution: 3.7 Å
Chemicals	ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying moleculeYM / Guanosine diphosphate 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 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 / medicationYM / Ponatinib ChemComp-919: 4-[4-({[3-tert-butyl-1-(quinolin-6-yl)-1H-pyrazol-5-yl]carbamoyl}amino)-3-fluorophenoxy]-N-methylpyridine-2-carboxamide
Source	homo sapiens (human)
Keywords	HYDROLASE/HYDROLASE INHIBITOR / Cryo-EM / Parkinson's disease / Kinase / LRRK2 / type I inhibitor / LRRK2-IN-1 / HYDROLASE-HYDROLASE INHIBITOR complex / HYDROLASE / type II inhibitor