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- PDB-6oje: Dimeric structure of LRRK2 GTPase domain -

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Basic information

Entry
Database: PDB / ID: 6oje
TitleDimeric structure of LRRK2 GTPase domain
ComponentsLeucine-rich repeat serine/threonine-protein kinase 2
KeywordsHYDROLASE / Parkinson's disease / LRRK2 / GTPase / Dimer / InterSwitch / complex
Function / homology
Function and homology information


caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb ...caveola neck / negative regulation of thioredoxin peroxidase activity by peptidyl-threonine phosphorylation / negative regulation of protein processing involved in protein targeting to mitochondrion / Wnt signalosome assembly / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / regulation of kidney size / regulation of neuron maturation / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / protein localization to endoplasmic reticulum exit site / GTP-dependent protein kinase activity / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / peroxidase inhibitor activity / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / negative regulation of protein targeting to mitochondrion / positive regulation of dopamine receptor signaling pathway / regulation of synaptic vesicle transport / regulation of CAMKK-AMPK signaling cascade / regulation of lysosomal lumen pH / amphisome / co-receptor binding / mitochondrion localization / negative regulation of excitatory postsynaptic potential / regulation of retrograde transport, endosome to Golgi / regulation of dopamine receptor signaling pathway / positive regulation of microglial cell activation / positive regulation of synaptic vesicle endocytosis / negative regulation of autophagosome assembly / cytoplasmic side of mitochondrial outer membrane / neuron projection arborization / regulation of cAMP/PKA signal transduction / olfactory bulb development / striatum development / multivesicular body, internal vesicle / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / JUN kinase kinase kinase activity / cellular response to dopamine / endoplasmic reticulum organization / positive regulation of protein autoubiquitination / Wnt signalosome / positive regulation of programmed cell death / negative regulation of protein processing / GTP metabolic process / syntaxin-1 binding / regulation of canonical Wnt signaling pathway / negative regulation of GTPase activity / exploration behavior / regulation of reactive oxygen species metabolic process / lysosome organization / clathrin binding / Golgi-associated vesicle / regulation of locomotion / protein kinase A binding / phosphorylation / negative regulation of macroautophagy / PTK6 promotes HIF1A stabilization / neuromuscular junction development / regulation of synaptic vesicle exocytosis / regulation of mitochondrial fission / Golgi organization / intracellular distribution of mitochondria / locomotory exploration behavior / regulation of synaptic vesicle endocytosis / endoplasmic reticulum exit site / autolysosome / microvillus / MAP kinase kinase kinase activity / negative regulation of Notch signaling pathway / positive regulation of protein kinase activity / Rho protein signal transduction / cellular response to manganese ion / canonical Wnt signaling pathway / presynaptic cytosol / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / regulation of synaptic transmission, glutamatergic / phagocytic vesicle / JNK cascade / positive regulation of autophagy / dendrite cytoplasm / negative regulation of protein binding / peptidyl-threonine phosphorylation / positive regulation of MAP kinase activity / tubulin binding / GTPase activator activity / SNARE binding / neuron projection morphogenesis / cellular response to starvation / positive regulation of protein ubiquitination / regulation of membrane potential / excitatory postsynaptic potential / determination of adult lifespan / cellular response to reactive oxygen species / mitochondrion organization / trans-Golgi network / calcium-mediated signaling / mitochondrial membrane
Similarity search - Function
LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc (COR) domain / C-terminal of Roc, COR-A domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type ...LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc (COR) domain / C-terminal of Roc, COR-A domain / Ras of Complex, Roc, domain of DAPkinase / Roc domain profile. / Roc domain / Leucine-rich repeats, bacterial type / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Rab subfamily of small GTPases / Leucine-rich repeat domain superfamily / Ankyrin repeat-containing domain superfamily / Armadillo-like helical / Small GTP-binding protein domain / Armadillo-type fold / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40-repeat-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / P-loop containing nucleoside triphosphate hydrolase
Similarity search - Domain/homology
GUANOSINE-5'-DIPHOSPHATE / Leucine-rich repeat serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 Å
AuthorsHoang, Q.Q. / Wu, C.X. / Liao, J. / Park, Y.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)1R01GM111639 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R01GM115844 United States
CitationJournal: To Be Published
Title: Structural basis for conformational plasticity in the GTPase domain of the Parkinson's disease-associated protein LRRK2
Authors: Wu, C.X. / Liao, J. / Park, Y. / Hoang, N.C. / Engel, V.A. / Sanishvili, R. / Takagi, Y. / Johnson, S.M. / Wang, M. / Federici, M. / Nichols, R.J. / Cookson, M.R. / Hoang, Q.Q.
History
DepositionApr 11, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 14, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 11, 2023Group: Advisory / Data collection ...Advisory / Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Leucine-rich repeat serine/threonine-protein kinase 2
B: Leucine-rich repeat serine/threonine-protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)48,0068
Polymers47,0222
Non-polymers9846
Water4,324240
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area7290 Å2
ΔGint-96 kcal/mol
Surface area18180 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.647, 103.688, 44.593
Angle α, β, γ (deg.)90.000, 101.200, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Leucine-rich repeat serine/threonine-protein kinase 2 / Dardarin / LRRK2


Mass: 23511.137 Da / Num. of mol.: 2 / Fragment: GTPase domain of leucine-rich repeat kinase 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: LRRK2, PARK8 / Plasmid: pETDuet1 / Production host: Escherichia coli BL21(DE3) (bacteria) / Variant (production host): Rosetta2
References: UniProt: Q5S007, non-specific serine/threonine protein kinase
#2: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: Mg
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 240 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.15 Å3/Da / Density % sol: 42.88 % / Mosaicity: 1.372 °
Crystal growTemperature: 298 K / Method: microbatch / pH: 6.5 / Details: 100mM KSCN, 25% PEGMME 2000, 0.1M BisTris pH 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 23-ID-D / Wavelength: 1.0331 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 12, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0331 Å / Relative weight: 1
ReflectionResolution: 1.9→50 Å / Num. obs: 31247 / % possible obs: 98.7 % / Redundancy: 6.1 % / Rmerge(I) obs: 0.072 / Rpim(I) all: 0.031 / Rrim(I) all: 0.078 / Χ2: 1.033 / Net I/σ(I): 5.6 / Num. measured all: 189486
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) allΧ2% possible all
1.9-1.934.30.45714530.8740.2330.5160.74591.7
1.93-1.9750.54614980.8830.2580.6060.51195.4
1.97-2.015.30.41415270.9230.1870.4560.45998
2.01-2.055.40.30115900.9620.1360.3310.46698
2.05-2.0960.27215230.9770.1180.2970.4798.4
2.09-2.146.30.25515940.9740.1080.2780.49299.6
2.14-2.196.40.23215330.9830.0980.2530.48898.7
2.19-2.256.40.30715740.9510.1320.3351.28199
2.25-2.326.40.22415380.980.0950.2440.99699.2
2.32-2.396.20.14115800.9940.060.1530.5699.4
2.39-2.4860.12215810.9920.0540.1340.67199.3
2.48-2.586.40.11315440.9940.0480.1230.7299.5
2.58-2.76.20.09515700.9950.0410.1040.70299.6
2.7-2.846.70.08915970.9940.0370.0970.78499.7
2.84-3.026.60.07515750.9960.0310.0820.99799.6
3.02-3.256.40.07215860.9940.0310.0781.48299.8
3.25-3.586.10.06715770.9940.030.0731.7599.6
3.58-4.096.30.0615890.9970.0260.0662.171100
4.09-5.166.60.05416010.9960.0240.062.058100
5.16-506.20.04916170.9970.0210.0532.19499.8

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0253refinement
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: RocCOR domain (3DPU)

3dpu


Resolution: 1.95→43.8 Å / Cor.coef. Fo:Fc: 0.962 / Cor.coef. Fo:Fc free: 0.95 / WRfactor Rfree: 0.1862 / WRfactor Rwork: 0.1476 / FOM work R set: 0.9024 / SU B: 3.426 / SU ML: 0.049 / SU R Cruickshank DPI: 0.0279 / SU Rfree: 0.0287 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R Free: 0.029 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.1962 1458 5.1 %RANDOM
Rwork0.1603 ---
obs0.1623 27245 99.1 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 140.73 Å2 / Biso mean: 46.293 Å2 / Biso min: 24.31 Å2
Baniso -1Baniso -2Baniso -3
1-8.28 Å20 Å27.23 Å2
2---13.9 Å2-0 Å2
3---5.62 Å2
Refinement stepCycle: final / Resolution: 1.95→43.8 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2893 0 60 249 3202
Biso mean--31.67 50.91 -
Num. residues----373
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0133097
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172894
X-RAY DIFFRACTIONr_angle_refined_deg1.3661.674202
X-RAY DIFFRACTIONr_angle_other_deg1.21.5966695
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9215389
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.55521.892148
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.80615556
X-RAY DIFFRACTIONr_dihedral_angle_4_deg12.9351521
X-RAY DIFFRACTIONr_chiral_restr0.0520.2416
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.023436
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02654
X-RAY DIFFRACTIONr_rigid_bond_restr1.12735991
LS refinement shellResolution: 1.95→2.001 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.079 125 -
Rwork0.069 1924 -
all-2049 -
obs--98.51 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.06430.0296-0.0170.0318-0.07750.27530.01250.0131-0.0035-0.00670.00720.00250.0478-0.0085-0.01970.0329-0.002-0.00110.0034-0.00050.0104-11.1665-2.858462.524
20.11520.07460.01260.0678-0.03950.1345-0.01960.0065-0.0227-0.00110.01-0.0218-0.0184-0.02450.00970.01970.00120.00080.00920.00030.01375.843711.713248.4261
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A1333 - 1518
2X-RAY DIFFRACTION2B1333 - 1519

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