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	Structure of LRRK2 in Parkinson's disease and model for microtubule interaction.
Journal, issue, pages	Nature, Vol. 588, Issue 7837, Page 344-349, Year 2020
Publish date	Aug 19, 2020
Authors	C K Deniston / J Salogiannis / S Mathea / D M Snead / I Lahiri / M Matyszewski / O Donosa / R Watanabe / J Böhning / A K Shiau / S Knapp / E Villa / S L Reck-Peterson / A E Leschziner /
PubMed Abstract	Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease and is also linked to its idiopathic form. LRRK2 has been proposed to function in membrane ...Leucine-rich repeat kinase 2 (LRRK2) is the most commonly mutated gene in familial Parkinson's disease and is also linked to its idiopathic form. LRRK2 has been proposed to function in membrane trafficking and colocalizes with microtubules. Despite the fundamental importance of LRRK2 for understanding and treating Parkinson's disease, structural information on the enzyme is limited. Here we report the structure of the catalytic half of LRRK2, and an atomic model of microtubule-associated LRRK2 built using a reported cryo-electron tomography in situ structure. We propose that the conformation of the LRRK2 kinase domain regulates its interactions with microtubules, with a closed conformation favouring oligomerization on microtubules. We show that the catalytic half of LRRK2 is sufficient for filament formation and blocks the motility of the microtubule-based motors kinesin 1 and cytoplasmic dynein 1 in vitro. Kinase inhibitors that stabilize an open conformation relieve this interference and reduce the formation of LRRK2 filaments in cells, whereas inhibitors that stabilize a closed conformation do not. Our findings suggest that LRRK2 can act as a roadblock for microtubule-based motors and have implications for the design of therapeutic LRRK2 kinase inhibitors.
External links	Nature / PubMed:32814344 / PubMed Central
Methods	EM (single particle)
Resolution	3.47 - 13.4 Å
Structure data	21250 6vno 6vp6 6vp7 6vp8 EMDB-21250, PDB-6vno, PDB-6vp6, PDB-6vp7, PDB-6vp8: Cryo-EM structure of the C-terminal half of the Parkinson's Disease-linked protein Leucine Rich Repeat Kinase 2 (LRRK2) Method: EM (single particle) / Resolution: 3.5 Å EMDB-21306: Cryo-EM map of the C-terminal half of Leucine Rich Repeat Kinase 2 as a monomer at 8.1 angstroms Method: EM (single particle) / Resolution: 8.1 Å EMDB-21309: Cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 as a COR-COR domain dimer at 9.5 angstroms Method: EM (single particle) / Resolution: 9.5 Å EMDB-21310: Cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 as a WD40-WD40 domain dimer at 13.4 angstroms Method: EM (single particle) / Resolution: 13.4 Å EMDB-21311: Cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 as a COR-COR domain dimer in the presence of the MLi-2 kinase inhibitor at 9.0 angstroms Method: EM (single particle) / Resolution: 9.0 Å EMDB-21312: Cryo-EM map of C-terminal half of Leucine Rich Repeat Kinase 2 as a WD40-WD40 domain dimer in the presence of the MLi-2 kinase inhibitor at 10.2 angstroms Method: EM (single particle) / Resolution: 10.2 Å
Chemicals	ChemComp-GDP: GUANOSINE-5'-DIPHOSPHATE / GDP, energy-carrying moleculeYM / Guanosine diphosphate ChemComp-MG*: Unknown entry
Source	homo sapiens (human)
Keywords	SIGNALING PROTEIN / Kinase / GTPase