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- PDB-7suf: Structure of CHK1 10-pt. mutant complex with LRRK2 inhibitor 06 -

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Basic information

Entry
Database: PDB / ID: 7suf
TitleStructure of CHK1 10-pt. mutant complex with LRRK2 inhibitor 06
ComponentsSerine/threonine-protein kinase Chk1
KeywordsTRANSFERASE/TRANSFERASE INHIBITOR / kinase / parkinson's disease / TRANSFERASE-TRANSFERASE INHIBITOR complex
Function / homology
Function and homology information


negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / regulation of mitotic centrosome separation / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization / negative regulation of gene expression, epigenetic ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / regulation of mitotic centrosome separation / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization / negative regulation of gene expression, epigenetic / Transcriptional Regulation by E2F6 / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / peptidyl-threonine phosphorylation / signal transduction in response to DNA damage / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Activation of ATR in response to replication stress / positive regulation of cell cycle / DNA damage checkpoint signaling / regulation of signal transduction by p53 class mediator / replication fork / condensed nuclear chromosome / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / TP53 Regulates Transcription of DNA Repair Genes / cellular response to mechanical stimulus / Signaling by SCF-KIT / G2/M DNA damage checkpoint / G2/M transition of mitotic cell cycle / regulation of cell population proliferation / Processing of DNA double-strand break ends / Regulation of TP53 Activity through Phosphorylation / DNA replication / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / chromatin remodeling / protein domain specific binding / protein serine kinase activity / DNA repair / intracellular membrane-bounded organelle / protein serine/threonine kinase activity / apoptotic process / DNA damage response / centrosome / chromatin / protein-containing complex / extracellular space / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Checkpoint kinase 1, catalytic domain / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / 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
Similarity search - Domain/homology
Chem-BVI / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.48 Å
AuthorsPalte, R.L.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2022
Title: Structure-Guided Discovery of Aminoquinazolines as Brain-Penetrant and Selective LRRK2 Inhibitors.
Authors: Keylor, M.H. / Gulati, A. / Kattar, S.D. / Johnson, R.E. / Chau, R.W. / Margrey, K.A. / Ardolino, M.J. / Zarate, C. / Poremba, K.E. / Simov, V. / Morriello, G.J. / Acton, J.J. / Pio, B. / ...Authors: Keylor, M.H. / Gulati, A. / Kattar, S.D. / Johnson, R.E. / Chau, R.W. / Margrey, K.A. / Ardolino, M.J. / Zarate, C. / Poremba, K.E. / Simov, V. / Morriello, G.J. / Acton, J.J. / Pio, B. / Yan, X. / Palte, R.L. / McMinn, S.E. / Nogle, L. / Lesburg, C.A. / Adpressa, D. / Lin, S. / Neelamkavil, S. / Liu, P. / Su, J. / Hegde, L.G. / Woodhouse, J.D. / Faltus, R. / Xiong, T. / Ciaccio, P.J. / Piesvaux, J. / Otte, K.M. / Wood, H.B. / Kennedy, M.E. / Bennett, D.J. / DiMauro, E.F. / Fell, M.J. / Fuller, P.H.
History
DepositionNov 17, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 12, 2022Provider: repository / Type: Initial release
Revision 1.1Jan 26, 2022Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Serine/threonine-protein kinase Chk1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,6926
Polymers34,0941
Non-polymers5985
Water4,234235
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.810, 65.950, 57.990
Angle α, β, γ (deg.)90.000, 94.120, 90.000
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Serine/threonine-protein kinase Chk1 / CHK1 checkpoint homolog / Cell cycle checkpoint kinase / Checkpoint kinase-1


Mass: 34094.207 Da / Num. of mol.: 1
Mutation: N59L, V68I, L84M, Y86L, C87A, E91S, E134H, S147A, F149Y, G150S
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CHEK1, CHK1 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O14757, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-BVI / 8-cyclopropyl-N-[5-methyl-1-(oxan-4-yl)-1H-pyrazol-4-yl]quinazolin-2-amine


Mass: 349.430 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H23N5O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 235 / 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: 2.51 Å3/Da / Density % sol: 50.93 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 11% PEG 8000, 15-20% ethylene glycol, 0.1 M MES (pH 6.5), 5% 6-aminohexanoic acid

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALBA / Beamline: XALOC / Wavelength: 0.9792 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 13, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9792 Å / Relative weight: 1
ReflectionResolution: 1.48→57.9 Å / Num. obs: 32368 / % possible obs: 80.5 % / Redundancy: 2.9 % / CC1/2: 0.987 / Net I/σ(I): 9.4
Reflection shellResolution: 1.483→1.61 Å / Num. unique obs: 1619 / CC1/2: 0.544

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Processing

Software
NameVersionClassification
PDB_EXTRACT3.27data extraction
autoPROCdata reduction
BUSTERrefinement
autoPROCdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5OOR

5oor


Resolution: 1.48→57.84 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.911 / SU B: 3.927 / SU ML: 0.074 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.133 / ESU R Free: 0.129 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2538 1624 5 %RANDOM
Rwork0.2168 ---
obs0.2187 30744 58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 70.81 Å2 / Biso mean: 22.392 Å2 / Biso min: 8.41 Å2
Baniso -1Baniso -2Baniso -3
1-0.14 Å2-0 Å20.16 Å2
2---0.04 Å20 Å2
3----0.12 Å2
Refinement stepCycle: final / Resolution: 1.48→57.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2130 0 42 235 2407
Biso mean--29.72 29.4 -
Num. residues----262
LS refinement shellResolution: 1.483→1.521 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 23 -
Rwork0.333 183 -
all-206 -
obs--5.06 %
Refinement TLS params.Method: refined / Origin x: 5.5369 Å / Origin y: -0.1637 Å / Origin z: 6.3827 Å
111213212223313233
T0.0092 Å20.0044 Å2-0.0023 Å2-0.0069 Å2-0.0064 Å2--0.049 Å2
L0.1635 °2-0.1186 °2-0.0694 °2-0.0974 °20.104 °2--0.4189 °2
S-0.0299 Å °0.0014 Å °-0.0196 Å °0.0281 Å °0.0072 Å °0.0088 Å °0.0342 Å °0.0202 Å °0.0227 Å °

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