+Open data
-Basic information
Entry | Database: PDB / ID: 8smc | ||||||
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Title | Cryo-EM structure of LRRK2 bound with type-I inhibitor DNL201 | ||||||
Components | non-specific serine/threonine protein kinase | ||||||
Keywords | HYDROLASE / Parkinson's Disease / kinase / activation | ||||||
Function / homology | Function and homology information GTP-dependent protein kinase activity / regulation of signal transduction / protein autophosphorylation / cell differentiation / non-specific serine/threonine protein kinase / protein phosphorylation / GTP binding / ATP binding / cytosol Similarity search - Function | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 4.02 Å | ||||||
Authors | Sun, J. / Zhu, H. | ||||||
Funding support | United States, 1items
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Citation | Journal: Science / Year: 2023 Title: Rab29-dependent asymmetrical activation of leucine-rich repeat kinase 2. Authors: Hanwen Zhu / Francesca Tonelli / Martin Turk / Alan Prescott / Dario R Alessi / Ji Sun / Abstract: Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles ...Gain-of-function mutations in , which encodes the leucine-rich repeat kinase 2 (LRRK2), are the most common genetic cause of late-onset Parkinson's disease. LRRK2 is recruited to membrane organelles and activated by Rab29, a Rab guanosine triphosphatase encoded in the locus. We present cryo-electron microscopy structures of Rab29-LRRK2 complexes in three oligomeric states, providing key snapshots during LRRK2 recruitment and activation. Rab29 induces an unexpected tetrameric assembly of LRRK2, formed by two kinase-active central protomers and two kinase-inactive peripheral protomers. The central protomers resemble the active-like state trapped by the type I kinase inhibitor DNL201, a compound that underwent a phase 1 clinical trial. Our work reveals the structural mechanism of LRRK2 spatial regulation and provides insights into LRRK2 inhibitor design for Parkinson's disease treatment. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 8smc.cif.gz | 197.6 KB | Display | PDBx/mmCIF format |
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PDB format | pdb8smc.ent.gz | 144.3 KB | Display | PDB format |
PDBx/mmJSON format | 8smc.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/sm/8smc ftp://data.pdbj.org/pub/pdb/validation_reports/sm/8smc | HTTPS FTP |
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-Related structure data
Related structure data | 40588MC 8fo2C 8fo8C 8fo9C M: map data used to model this data C: citing same article (ref.) |
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Similar structure data | Similarity search - Function & homologyF&H Search |
-Links
-Assembly
Deposited unit |
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1 |
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-Components
#1: Protein | Mass: 136843.469 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) Homo sapiens (human) / Gene: LRRK2 / Production host: Homo sapiens (human) / References: UniProt: Q17RV3 |
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#2: Chemical | ChemComp-GDP / |
#3: Chemical | ChemComp-TVT / |
Has ligand of interest | Y |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
-Sample preparation
Component | Name: LRRK2 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Source (natural) | Organism: Homo sapiens (human) |
Source (recombinant) | Organism: Homo sapiens (human) |
Buffer solution | pH: 8 |
Specimen | Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES |
Vitrification | Cryogen name: ETHANE |
-Electron microscopy imaging
Experimental equipment | Model: Titan Krios / Image courtesy: FEI Company |
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Microscopy | Model: FEI TITAN KRIOS |
Electron gun | Electron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2800 nm / Nominal defocus min: 1000 nm |
Image recording | Electron dose: 1 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) |
-Processing
EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | |||||||||
Symmetry | Point symmetry: C1 (asymmetric) | |||||||||
3D reconstruction | Resolution: 4.02 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 59515 / Symmetry type: POINT | |||||||||
Atomic model building | Protocol: OTHER |