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- PDB-6xaf: 1.9A crystal structure of the GTPase domain of Parkinson's diseas... -

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Basic information

Entry
Database: PDB / ID: 6xaf
Title1.9A crystal structure of the GTPase domain of Parkinson's disease-associated protein LRRK2 carrying R1398H
ComponentsLeucine-rich repeat serine/threonine-protein kinase 2
KeywordsHYDROLASE / Parkinson's disease / LRRK2 / GTPase / Dimer / InterSwitch / complex
Function / homology
Function and homology information


peroxidase inhibitor activity / 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 / tangential migration from the subventricular zone to the olfactory bulb ...peroxidase inhibitor activity / 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 / 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 / regulation of synaptic vesicle transport / 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 lysosomal lumen pH / regulation of CAMKK-AMPK signaling cascade / amphisome / mitochondrion localization / cytoplasmic side of mitochondrial outer membrane / co-receptor binding / regulation of retrograde transport, endosome to Golgi / negative regulation of excitatory postsynaptic potential / negative regulation of autophagosome assembly / regulation of dopamine receptor signaling pathway / positive regulation of microglial cell activation / neuron projection arborization / positive regulation of synaptic vesicle endocytosis / JUN kinase kinase kinase activity / olfactory bulb development / regulation of protein kinase A signaling / multivesicular body, internal vesicle / striatum development / regulation of dendritic spine morphogenesis / protein localization to mitochondrion / cellular response to dopamine / presynaptic cytosol / positive regulation of protein autoubiquitination / endoplasmic reticulum organization / positive regulation of programmed cell death / regulation of canonical Wnt signaling pathway / Wnt signalosome / GTP metabolic process / negative regulation of protein processing / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / negative regulation of GTPase activity / exploration behavior / autolysosome / protein kinase A binding / regulation of locomotion / regulation of synaptic vesicle exocytosis / Golgi-associated vesicle / negative regulation of macroautophagy / PTK6 promotes HIF1A stabilization / clathrin binding / neuromuscular junction development / lysosome organization / regulation of mitochondrial fission / intracellular distribution of mitochondria / Golgi organization / positive regulation of nitric-oxide synthase biosynthetic process / locomotory exploration behavior / microvillus / endoplasmic reticulum exit site / Rho protein signal transduction / MAP kinase kinase kinase activity / positive regulation of protein kinase activity / canonical Wnt signaling pathway / cellular response to manganese ion / positive regulation of autophagy / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / JNK cascade / regulation of synaptic transmission, glutamatergic / cellular response to starvation / excitatory postsynaptic potential / dendrite cytoplasm / mitochondrion organization / tubulin binding / GTPase activator activity / SNARE binding / neuron projection morphogenesis / negative regulation of protein phosphorylation / negative regulation of protein binding / positive regulation of protein ubiquitination / regulation of membrane potential / regulation of autophagy / calcium-mediated signaling / determination of adult lifespan / mitochondrial membrane / Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement / peptidyl-threonine phosphorylation / positive regulation of MAP kinase activity / trans-Golgi network / regulation of protein stability / protein localization
Similarity search - Function
C-terminal of Roc (COR) domain / C-terminal of Roc, COR, 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. ...C-terminal of Roc (COR) domain / C-terminal of Roc, COR, 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 / WD40-repeat-containing domain superfamily / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / WD40/YVTN repeat-like-containing domain superfamily / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / 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 / Resolution: 1.968 Å
AuthorsHoang, Q.Q. / Liao, J. / Huang, X. / Park, Y. / Wu, C.X.
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
DepositionJun 4, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 9, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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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)47,6876
Polymers46,7522
Non-polymers9354
Water2,414134
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area6820 Å2
ΔGint-74 kcal/mol
Surface area16240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.497, 101.785, 44.527
Angle α, β, γ (deg.)90.000, 101.380, 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


Mass: 23375.887 Da / Num. of mol.: 2 / Fragment: GTPase domain (UNP residues 1329-1520) / Mutation: R1398H, K1460A, K1463A
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, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement
#2: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE / Guanosine diphosphate


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Feature type: SUBJECT OF INVESTIGATION / Comment: GDP, energy-carrying molecule*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 134 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.11 Å3/Da / Density % sol: 41.83 %
Crystal growTemperature: 298 K / Method: microbatch / pH: 6.5
Details: 100 mM potassium thiocyanate, 25% PEG2000 MME, 0.1 M Bis-Tris, 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 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 7, 2018
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.96→20.05 Å / Num. obs: 27384 / % possible obs: 99.35 % / Redundancy: 3.3 % / Biso Wilson estimate: 29.64 Å2 / CC1/2: 0.968 / Rpim(I) all: 0.062 / Rrim(I) all: 0.115 / Net I/σ(I): 13.64
Reflection shellResolution: 1.96→1.99 Å / Num. unique obs: 2565 / CC1/2: 0.862

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Processing

Software
NameVersionClassification
PHENIX1.13_2998refinement
HKL-2000data scaling
PDB_EXTRACT3.25data extraction
HKL-2000data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 6OJF

6ojf


Resolution: 1.968→20.048 Å / SU ML: 0.19 / Cross valid method: THROUGHOUT / σ(F): 1.38 / Phase error: 24.04 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2214 1998 7.3 %
Rwork0.1804 25382 -
obs0.1834 27380 99.34 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 135.65 Å2 / Biso mean: 43.7206 Å2 / Biso min: 16.77 Å2
Refinement stepCycle: final / Resolution: 1.968→20.048 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2684 0 58 134 2876
Biso mean--27.99 40.72 -
Num. residues----346
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
1.968-2.01670.25131370.1968175495
2.0167-2.07110.25611330.1971177899
2.0711-2.1320.2471470.19451842100
2.132-2.20080.25911390.20121787100
2.2008-2.27930.21851440.18081820100
2.2793-2.37040.24521440.1741823100
2.3704-2.47810.23141410.18211836100
2.4781-2.60850.24281440.18321805100
2.6085-2.77160.26541430.20261831100
2.7716-2.98490.22561440.19761821100
2.9849-3.28410.24371440.19111807100
3.2841-3.75660.21041460.17371834100
3.7566-4.72270.17131430.15271810100
4.7227-20.0480.21711490.1815183499
Refinement TLS params.Method: refined / Origin x: 10.0919 Å / Origin y: -5.4809 Å / Origin z: 9.5039 Å
111213212223313233
T0.227 Å20.0258 Å2-0.0273 Å2-0.1809 Å2-0.0154 Å2--0.2086 Å2
L2.4513 °20.7327 °2-1.0519 °2-1.0303 °2-0.6779 °2--1.9019 °2
S0.0081 Å °0.1244 Å °0.1014 Å °-0.0031 Å °0.0114 Å °0.0007 Å °-0.0103 Å °-0.1254 Å °-0.0116 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA1335 - 1514
2X-RAY DIFFRACTION1allB1334 - 1515
3X-RAY DIFFRACTION1allD1 - 2
4X-RAY DIFFRACTION1allC1 - 2
5X-RAY DIFFRACTION1allS1 - 133
6X-RAY DIFFRACTION1allS134

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