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- PDB-9c76: LRRK2 Roc domain RP (Ras-pocket) complexed to Divarasib -

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Basic information

Entry
Database: PDB / ID: 9c76
TitleLRRK2 Roc domain RP (Ras-pocket) complexed to Divarasib
ComponentsLeucine-rich repeat serine/threonine-protein kinase 2
KeywordsSIGNALING PROTEIN / GTPase / Complex / chemical biology / switch II
Function / homology
Function and homology information


caveola neck / : / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / Wnt signalosome assembly / regulation of kidney size / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / GTP-dependent protein kinase activity / regulation of SNARE complex assembly ...caveola neck / : / beta-catenin destruction complex binding / regulation of branching morphogenesis of a nerve / Wnt signalosome assembly / regulation of kidney size / regulation of cell projection organization / tangential migration from the subventricular zone to the olfactory bulb / GTP-dependent protein kinase activity / regulation of SNARE complex assembly / regulation of neuroblast proliferation / regulation of ER to Golgi vesicle-mediated transport / protein localization to endoplasmic reticulum exit site / peroxidase inhibitor activity / negative regulation of late endosome to lysosome transport / regulation of mitochondrial depolarization / : / positive regulation of dopamine receptor signaling pathway / amphisome / regulation of synaptic vesicle transport / regulation of lysosomal lumen pH / regulation of CAMKK-AMPK signaling cascade / co-receptor binding / negative regulation of GTPase activity / regulation of dopamine receptor signaling pathway / positive regulation of microglial cell activation / regulation of neuron maturation / regulation of retrograde transport, endosome to Golgi / positive regulation of synaptic vesicle endocytosis / negative regulation of excitatory postsynaptic potential / cytoplasmic side of mitochondrial outer membrane / negative regulation of autophagosome assembly / olfactory bulb development / JUN kinase kinase kinase activity / neuron projection arborization / striatum development / multivesicular body, internal vesicle / regulation of dendritic spine morphogenesis / mitochondrion localization / protein localization to mitochondrion / cellular response to dopamine / positive regulation of mitochondrial outer membrane permeabilization involved in apoptotic signaling pathway / endoplasmic reticulum organization / positive regulation of protein autoubiquitination / Wnt signalosome / negative regulation of protein processing / positive regulation of programmed cell death / GTP metabolic process / regulation of canonical Wnt signaling pathway / syntaxin-1 binding / regulation of reactive oxygen species metabolic process / lysosome organization / Golgi-associated vesicle / clathrin binding / PTK6 promotes HIF1A stabilization / negative regulation of macroautophagy / neuromuscular junction development / regulation of cAMP/PKA signal transduction / protein kinase A binding / regulation of mitochondrial fission / regulation of locomotion / regulation of synaptic vesicle exocytosis / Golgi organization / intracellular distribution of mitochondria / microvillus / exploration behavior / endoplasmic reticulum exit site / autolysosome / locomotory exploration behavior / negative regulation of Notch signaling pathway / regulation of synaptic vesicle endocytosis / MAP kinase kinase kinase activity / canonical Wnt signaling pathway / regulation of synaptic transmission, glutamatergic / negative regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway / Rho protein signal transduction / presynaptic cytosol / neuron projection morphogenesis / phagocytic vesicle / cellular response to manganese ion / JNK cascade / positive regulation of autophagy / dendrite cytoplasm / tubulin binding / GTPase activator activity / cellular response to starvation / positive regulation of protein ubiquitination / SNARE binding / determination of adult lifespan / regulation of membrane potential / cellular response to reactive oxygen species / excitatory postsynaptic potential / mitochondrion organization / trans-Golgi network / calcium-mediated signaling / regulation of protein stability / autophagy / small GTPase binding / mitochondrial membrane / endocytosis
Similarity search - Function
: / : / : / LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc, COR-B domain / C-terminal of Roc (COR) domain / C-terminal of Roc, COR-A domain ...: / : / : / LRRK2 ARM repeat / LRRK2 ANK repeat / LRRK2 beta propeller / : / C-terminal of Roc, COR-B domain / 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. / Protein kinase domain / WD40-repeat-containing domain superfamily / 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
: / BROMIDE ION / FLUORIDE ION / GUANOSINE-5'-DIPHOSPHATE / IODIDE ION / Leucine-rich repeat serine/threonine-protein kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsZhu, L.Y. / Guiley, K.Z. / Shokat, K.M.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)F31NS122434 United States
Michael J. Fox Foundation17461 United States
CitationJournal: To Be Published
Title: LRRK2 Roc domain RP (Ras-pocket) complexed to Divarasib
Authors: Zhu, L.Y. / Shokat, K.M.
History
DepositionJun 10, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: Structure summary / Category: audit_author / Item: _audit_author.name

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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)45,47613
Polymers42,9082
Non-polymers2,56911
Water1,72996
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)40.411, 98.379, 105.203
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and (resid 3 through 29 or (resid 41...
d_2ens_1(chain "B" and (resid 3 through 24 or (resid 25...
d_1ens_2chain "C"
d_2ens_2chain "D"
d_1ens_3chain "G"
d_2ens_3chain "H"

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1VALVALLYSLYSAA3 - 293 - 29
d_12ens_1THRTHRARGARGAA41 - 18741 - 187
d_21ens_1VALVALLYSLYSBB3 - 293 - 29
d_22ens_1THRTHRGLYGLYBB41 - 9741 - 97
d_23ens_1GLUGLUVALVALBB100 - 129100 - 129
d_24ens_1GLUGLUTHRTHRBB132 - 143132 - 143
d_25ens_1LEULEULEULEUBB146 - 147146 - 147
d_26ens_1PROPROARGARGBB153 - 187153 - 187
d_11ens_2GDPGDPGDPGDPCC1
d_21ens_2GDPGDPGDPGDPDD1
d_11ens_3LRJLRJLRJLRJGL1
d_21ens_3LRJLRJLRJLRJHM1

NCS ensembles :
ID
ens_1
ens_2
ens_3

NCS oper:
IDCodeMatrixVector
1given(0.465516363205, 0.881275749353, 0.0815326265386), (0.877988912895, -0.471449110277, 0.082892733413), (0.111489839995, 0.0329968183455, -0.993217612388)4.30014974406, -4.5823768633, -22.2398627674
2given(0.432032194611, 0.888980504899, 0.151861268037), (0.87545780057, -0.453841115009, 0.166138140561), (0.216614455291, 0.0611711062321, -0.97433889049)4.38083380262, -3.75553967892, -20.7865631355
3given(0.534059721438, 0.825320637191, 0.183374097855), (0.836240762657, -0.483748603221, -0.258241506644), (-0.124425081108, 0.291261282544, -0.948517403363)4.54514299617, -9.56938874326, -17.2827201949

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 21453.811 Da / Num. of mol.: 2 / Fragment: Roc domain
Mutation: N1342A, T1343C, P1433H, W1434Y, N1437Q, K1460A, K1463A, C1465A (Uniprot numbering)
Source method: isolated from a genetically manipulated source
Details: N-His-TEV protein, cleaved / Source: (gene. exp.) Homo sapiens (human) / Gene: LRRK2, PARK8 / Production host: Escherichia coli (E. coli)
References: UniProt: Q5S007, non-specific serine/threonine protein kinase, Hydrolases; Acting on acid anhydrides; Acting on GTP to facilitate cellular and subcellular movement

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Non-polymers , 7 types, 107 molecules

#2: Chemical ChemComp-GDP / GUANOSINE-5'-DIPHOSPHATE


Type: RNA linking / Mass: 443.201 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H15N5O11P2 / Comment: GDP, energy-carrying molecule*YM
#3: Chemical ChemComp-BR / BROMIDE ION


Mass: 79.904 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Br
#4: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#5: Chemical ChemComp-F / FLUORIDE ION


Mass: 18.998 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: F
#6: Chemical ChemComp-A1AWR / 1-{(3S)-4-[(7M)-7-[6-amino-4-methyl-3-(trifluoromethyl)pyridin-2-yl]-6-chloro-8-fluoro-2-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}quinazolin-4-yl]-3-methylpiperazin-1-yl}propan-1-one / divarasib, bound form


Mass: 624.073 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C29H34ClF4N7O2 / Feature type: SUBJECT OF INVESTIGATION
#7: Chemical ChemComp-IOD / IODIDE ION


Mass: 126.904 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: I
#8: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 96 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationY

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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: 2.41 Å3/Da / Density % sol: 48.9 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: Morpheus Fusion C7: 30 mM Halides 0.12 M Monosaccharide 1 0.1 M Buffer System 1 pH 6.5 30% Precipitant mix 1

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 2.0.1 / Wavelength: 1.02808 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 13, 2023
RadiationMonochromator: M / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.02808 Å / Relative weight: 1
ReflectionResolution: 2.3→49.19 Å / Num. obs: 19323 / % possible obs: 99.8 % / Redundancy: 6.2 % / CC1/2: 0.978 / Rpim(I) all: 0.129 / Rrim(I) all: 0.332 / Net I/σ(I): 9.9
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 6.4 % / Mean I/σ(I) obs: 2.4 / Num. unique obs: 1866 / CC1/2: 0.715 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX1.21.1_5286refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.3→35.22 Å / SU ML: 0.3217 / Cross valid method: FREE R-VALUE / Phase error: 28.163
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2668 1935 10.04 %
Rwork0.2268 17332 -
obs0.231 19267 99.62 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 53.74 Å2
Refinement stepCycle: LAST / Resolution: 2.3→35.22 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2644 0 149 96 2889
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00512843
X-RAY DIFFRACTIONf_angle_d0.80973863
X-RAY DIFFRACTIONf_chiral_restr0.0495439
X-RAY DIFFRACTIONf_plane_restr0.0089470
X-RAY DIFFRACTIONf_dihedral_angle_d17.13881029
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS2.37059230065
ens_2d_2CAX-RAY DIFFRACTIONTorsion NCS0.401307939839
ens_3d_2MBX-RAY DIFFRACTIONTorsion NCS1.49614063499
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.3-2.360.33291250.29111235X-RAY DIFFRACTION99.56
2.36-2.420.33381540.26941164X-RAY DIFFRACTION99.85
2.42-2.490.30781360.28611225X-RAY DIFFRACTION99.71
2.49-2.570.30921190.26351237X-RAY DIFFRACTION99.93
2.57-2.660.36581500.27911220X-RAY DIFFRACTION99.85
2.66-2.770.30061240.28611229X-RAY DIFFRACTION99.71
2.77-2.90.30171430.25271236X-RAY DIFFRACTION99.71
2.9-3.050.30041320.26351217X-RAY DIFFRACTION99.78
3.05-3.240.34581450.24811218X-RAY DIFFRACTION99.85
3.24-3.490.27491330.23641249X-RAY DIFFRACTION99.86
3.49-3.840.25461360.20391242X-RAY DIFFRACTION99.78
3.84-4.40.2241420.19061265X-RAY DIFFRACTION99.58
4.4-5.530.21351440.18071274X-RAY DIFFRACTION99.65
5.54-35.220.23771520.22011321X-RAY DIFFRACTION98.07

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