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	Inhibition of Parkinson's disease-related LRRK2 by type I and type II kinase inhibitors: Activity and structures.
Journal, issue, pages	Sci Adv, Vol. 9, Issue 48, Page eadk6191, Year 2023
Publish date	Dec 1, 2023
Authors	Marta Sanz Murillo / Amalia Villagran Suarez / Verena Dederer / Deep Chatterjee / Jaime Alegrio Louro / Stefan Knapp / Sebastian Mathea / Andres E Leschziner /
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 ...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.
External links	Sci Adv / PubMed:38039358 / PubMed Central
Methods	EM (single particle)
Resolution	2.7 - 3.9 Å
Structure data	41709 8txz EMDB-41709, PDB-8txz: Structure of C-terminal LRRK2 bound to MLi-2 Method: EM (single particle) / Resolution: 3.05 Å 41728 8tyq EMDB-41728, PDB-8tyq: Structure of the C-terminal half of LRRK2 bound to GZD-824 (G2019S mutant) Method: EM (single particle) / Resolution: 2.99 Å 41753 8tzb EMDB-41753, PDB-8tzb: Structure of the C-terminal half of LRRK2 bound to GZD-824 (I2020T mutant) Method: EM (single particle) / Resolution: 3.1 Å 41754 8tzc EMDB-41754, PDB-8tzc: Structure of C-terminal LRRK2 bound to MLi-2 (G2019S mutant) Method: EM (single particle) / Resolution: 2.7 Å 41756 8tze EMDB-41756, PDB-8tze: Structure of C-terminal half of LRRK2 bound to GZD-824 Method: EM (single particle) / Resolution: 2.9 Å 41757 8tzf EMDB-41757, PDB-8tzf: Structure of full length LRRK2 bound to GZD-824 (I2020T mutant) Method: EM (single particle) / Resolution: 3.4 Å 41758 8tzg EMDB-41758, PDB-8tzg: Structure of C-terminal LRRK2 bound to MLi-2 (I2020T mutant) Method: EM (single particle) / Resolution: 2.7 Å 41759 8tzh EMDB-41759, PDB-8tzh: Structure of full-length LRRK2 bound to MLi-2 (I2020T mutant) Method: EM (single particle) / Resolution: 3.9 Å EMDB-41794: Structure of C-terminal half of LRRK2 (I2020T mutant) bound to GZD-824, Kinase-WD40 Method: EM (single particle) / Resolution: 3.06 Å EMDB-41795: Structure of C-terminal half of LRRK2 (I2020T mutant) bound to GZD-824, ROC-COR domain Method: EM (single particle) / Resolution: 3.63 Å EMDB-41797: Structure of C-terminal half of LRRK2 (G2019S mutant) bound to GZD-824, ROC-COR domain Method: EM (single particle) / Resolution: 3.5 Å EMDB-41798: Structure of C-terminal half of LRRK2 bound tp GZFD-824 (G2019S mutant) Method: EM (single particle) / Resolution: 3.1 Å EMDB-41799: Structure of C-terminal half of LRRK2 bound to GZD-824 (G2019S mutant), Kinase-WD40 Method: EM (single particle) / Resolution: 2.99 Å EMDB-41802: Structure of C-terminal half of LRRK2 bound to GZD-824 (I2020T mutant) Method: EM (single particle) / Resolution: 3.22 Å
Chemicals	ChemComp-A1N: (2~{R},6~{S})-2,6-dimethyl-4-[6-[5-(1-methylcyclopropyl)oxy-1~{H}-indazol-3-yl]pyrimidin-4-yl]morpholine ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying moleculeYM 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
Source	homo sapiens (human) synthetic construct (others)
Keywords	PROTEIN BINDING / GTPase / kinase / inhibitors / Kinase inhibitors / GTPases