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Open data
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Basic information
Entry | Database: PDB / ID: 8fac | ||||||
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Title | Structure of the leucine-rich repeat kinase 1 monomer | ||||||
![]() | Leucine-rich repeat serine/threonine-protein kinase 1 | ||||||
![]() | TRANSFERASE / kinase / LRRK / multi-domain protein / GTPase | ||||||
Function / homology | ![]() negative regulation of peptidyl-tyrosine phosphorylation / positive regulation of intracellular signal transduction / osteoclast development / bone resorption / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity ...negative regulation of peptidyl-tyrosine phosphorylation / positive regulation of intracellular signal transduction / osteoclast development / bone resorption / positive regulation of peptidyl-tyrosine phosphorylation / positive regulation of canonical Wnt signaling pathway / non-specific serine/threonine protein kinase / intracellular signal transduction / phosphorylation / protein serine kinase activity / protein serine/threonine kinase activity / GTP binding / mitochondrion / ATP binding / identical protein binding / membrane / metal ion binding / cytosol Similarity search - Function | ||||||
Biological species | ![]() | ||||||
Method | ELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.92 Å | ||||||
![]() | Metcalfe, R.D. / Martinez Fiesco, J.A. / Zhang, P. | ||||||
Funding support | ![]()
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![]() | ![]() Title: Structure and regulation of full-length human leucine-rich repeat kinase 1. Authors: Riley D Metcalfe / Juliana A Martinez Fiesco / Luis Bonet-Ponce / Jillian H Kluss / Mark R Cookson / Ping Zhang / ![]() Abstract: The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human ...The human leucine-rich repeat kinases (LRRKs), LRRK1 and LRRK2 are large and unusually complex multi-domain kinases, which regulate fundamental cellular processes and have been implicated in human disease. Structures of LRRK2 have recently been determined, but the structure and molecular mechanisms regulating the activity of the LRRK1 as well as differences in the regulation of LRRK1 and LRRK2 remain unclear. Here, we report a cryo-EM structure of the LRRK1 monomer and a lower-resolution cryo-EM map of the LRRK1 dimer. The monomer structure, in which the kinase is in an inactive conformation, reveals key interdomain interfaces that control kinase activity as we validate experimentally. Both the LRRK1 monomer and dimer are structurally distinct compared to LRRK2. Overall, our results provide structural insights into the activation of the human LRRKs, which advance our understanding of their physiological and pathological roles. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 318.8 KB | Display | ![]() |
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PDB format | ![]() | 203.6 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
Others | ![]() |
-Validation report
Summary document | ![]() | 891.3 KB | Display | ![]() |
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Full document | ![]() | 910.5 KB | Display | |
Data in XML | ![]() | 44 KB | Display | |
Data in CIF | ![]() | 65.9 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 28950MC C: citing same article ( M: map data used to model this data |
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Similar structure data | Similarity search - Function & homology ![]() |
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Links
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Assembly
Deposited unit | ![]()
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1 |
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Components
#1: Protein | Mass: 229556.359 Da / Num. of mol.: 1 Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: Q38SD2, non-specific serine/threonine protein kinase |
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#2: Chemical | ChemComp-GDP / |
Has ligand of interest | N |
-Experimental details
-Experiment
Experiment | Method: ELECTRON MICROSCOPY |
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EM experiment | Aggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction |
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Sample preparation
Component | Name: Leucine-rich repeat kinase 1 / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT |
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Molecular weight | Value: 0.23 MDa / Experimental value: YES |
Source (natural) | Organism: ![]() |
Source (recombinant) | Organism: ![]() ![]() |
Buffer solution | pH: 8.3 |
Specimen | Conc.: 0.2 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES / Details: Purified LRRK1 |
Vitrification | Instrument: LEICA EM GP / Cryogen name: ETHANE |
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Electron microscopy imaging
Experimental equipment | ![]() Model: Talos Arctica / Image courtesy: FEI Company |
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Microscopy | Model: FEI TALOS ARCTICA |
Electron gun | Electron source: ![]() |
Electron lens | Mode: BRIGHT FIELD / Nominal defocus max: 2500 nm / Nominal defocus min: 800 nm |
Image recording | Average exposure time: 2.5 sec. / Electron dose: 50 e/Å2 / Film or detector model: GATAN K3 (6k x 4k) / Num. of grids imaged: 7 / Num. of real images: 18074 |
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Processing
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EM software |
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CTF correction | Type: PHASE FLIPPING AND AMPLITUDE CORRECTION | ||||||||||||||||||||||||
Particle selection | Num. of particles selected: 3553719 Details: Particles picked using a Topaz model trained on an initial LRRK1 dataset. | ||||||||||||||||||||||||
3D reconstruction | Resolution: 3.92 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 183273 Details: Resolution given for map is the resolution of the global refinement map (D_1000269296). The resolution for the local refinement map was 3.94 (D_1000269298). Symmetry type: POINT | ||||||||||||||||||||||||
Refinement | Cross valid method: NONE Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2 | ||||||||||||||||||||||||
Displacement parameters | Biso mean: 66.06 Å2 | ||||||||||||||||||||||||
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