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- PDB-5op2: Structure of CHK1 10-pt. mutant complex with arylbenzamide LRRK2 ... -

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Basic information

Entry
Database: PDB / ID: 5op2
TitleStructure of CHK1 10-pt. mutant complex with arylbenzamide LRRK2 inhibitor
ComponentsSerine/threonine-protein kinase Chk1
KeywordsTRANSFERASE / Parkinson's disease / Leucine-rich repeat kinase 2 / LRRK2 / Checkpoint kinase 1 / CHK1 / mutant / surrogate / kinase inhibitor
Function / homology
Function and homology information


negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / mitotic G2/M transition checkpoint / negative regulation of mitotic nuclear division / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / mitotic G2/M transition checkpoint / negative regulation of mitotic nuclear division / regulation of mitotic centrosome separation / inner cell mass cell proliferation / regulation of double-strand break repair via homologous recombination / nucleus organization / negative regulation of gene expression, epigenetic / cellular response to caffeine / Transcriptional Regulation by E2F6 / mitotic G2 DNA damage checkpoint signaling / Presynaptic phase of homologous DNA pairing and strand exchange / replicative senescence / signal transduction in response to DNA damage / positive regulation of cell cycle / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / Activation of ATR in response to replication stress / regulation of signal transduction by p53 class mediator / DNA damage checkpoint signaling / condensed nuclear chromosome / replication fork / TP53 Regulates Transcription of DNA Repair Genes / peptidyl-threonine phosphorylation / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / Signaling by SCF-KIT / G2/M DNA damage checkpoint / cellular response to mechanical stimulus / 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 / non-specific serine/threonine protein kinase / protein kinase activity / chromatin remodeling / protein phosphorylation / protein domain specific binding / intracellular membrane-bounded organelle / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / DNA damage response / chromatin / apoptotic process / protein-containing complex / extracellular space / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Checkpoint kinase 1, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 ...Checkpoint kinase 1, catalytic domain / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-A0Q / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsDokurno, P. / Williamson, D.S. / Acheson-Dossang, P. / Chen, I. / Murray, J.B. / Shaw, T. / Surgenor, A.E.
CitationJournal: J. Med. Chem. / Year: 2017
Title: Design of Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Crystallographic Surrogate Derived from Checkpoint Kinase 1 (CHK1).
Authors: Williamson, D.S. / Smith, G.P. / Acheson-Dossang, P. / Bedford, S.T. / Chell, V. / Chen, I.J. / Daechsel, J.C.A. / Daniels, Z. / David, L. / Dokurno, P. / Hentzer, M. / Herzig, M.C. / ...Authors: Williamson, D.S. / Smith, G.P. / Acheson-Dossang, P. / Bedford, S.T. / Chell, V. / Chen, I.J. / Daechsel, J.C.A. / Daniels, Z. / David, L. / Dokurno, P. / Hentzer, M. / Herzig, M.C. / Hubbard, R.E. / Moore, J.D. / Murray, J.B. / Newland, S. / Ray, S.C. / Shaw, T. / Surgenor, A.E. / Terry, L. / Thirstrup, K. / Wang, Y. / Christensen, K.V.
History
DepositionAug 9, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 25, 2017Provider: repository / Type: Initial release
Revision 1.1Nov 22, 2017Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 2024Group: 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,5684
Polymers34,0941
Non-polymers4733
Water3,585199
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area270 Å2
ΔGint-18 kcal/mol
Surface area12900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.130, 66.080, 55.180
Angle α, β, γ (deg.)90.000, 99.300, 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 / Plasmid: Pfastbac1 / Cell line (production host): SF9 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: O14757, non-specific serine/threonine protein kinase
#2: Chemical ChemComp-A0Q / 5-(4-methylpiperazin-1-yl)-2-phenylmethoxy-~{N}-pyridin-3-yl-benzamide


Mass: 402.489 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26N4O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 199 / Source method: isolated from a natural source / Formula: H2O

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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: 2.38 Å3/Da / Density % sol: 48.35 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 7% PEG 8000, 0.1 M MES buffer pH 6.5, 20% ethylene glycol

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.97932 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Nov 10, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97932 Å / Relative weight: 1
ReflectionResolution: 1.83→54.458 Å / Num. all: 27663 / Num. obs: 27663 / % possible obs: 97.8 % / Redundancy: 3.3 % / Rpim(I) all: 0.03 / Rrim(I) all: 0.055 / Rsym value: 0.046 / Net I/av σ(I): 11.3 / Net I/σ(I): 15.9 / Num. measured all: 90466
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique obsRpim(I) allRrim(I) allRsym value% possible all
1.83-1.892.60.3552.223460.2670.4470.35585.7
1.89-1.973.20.2932.626330.1940.3520.29398
1.97-2.053.40.233.225660.1460.2730.2399.4
2.05-2.143.40.1664.324380.1050.1970.16699.5
2.14-2.243.20.1285.523060.0840.1540.12898.8
2.24-2.363.50.0947.422520.0590.1110.09499.3
2.36-2.513.40.0779.121250.0490.0920.07799.4
2.51-2.683.30.0611.719730.0390.0710.0699.3
2.68-2.893.40.04814.418450.0310.0570.04899.1
2.89-3.173.40.03917.217020.0250.0460.03999.2
3.17-3.543.20.03319.315270.0220.040.03398.7
3.54-4.093.40.02920.813810.0180.0340.02999.2
4.09-5.013.30.02820.911550.0180.0330.02899.1
5.01-7.093.20.02722.99040.0180.0320.02799.5
7.09-54.4583.20.02820.15100.0190.0340.02898.6

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Processing

Software
NameVersionClassification
SCALA3.3.16data scaling
REFMAC5.8.0158refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5OOP

5oop


Resolution: 1.9→44.54 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.951 / SU B: 2.838 / SU ML: 0.083 / SU R Cruickshank DPI: 0.1244 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.124 / ESU R Free: 0.122
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2 1253 5 %RANDOM
Rwork0.1593 ---
obs0.1613 23831 98.98 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 118.51 Å2 / Biso mean: 33.797 Å2 / Biso min: 13.64 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0 Å2-0.01 Å2
2--0.01 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 1.9→44.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2110 0 32 199 2341
Biso mean--36.67 40.61 -
Num. residues----263
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.020.0192198
X-RAY DIFFRACTIONr_bond_other_d0.0020.022054
X-RAY DIFFRACTIONr_angle_refined_deg1.9471.9792980
X-RAY DIFFRACTIONr_angle_other_deg1.1353.0024740
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.55263
X-RAY DIFFRACTIONr_dihedral_angle_2_deg38.46424.5100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.3115382
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.861512
X-RAY DIFFRACTIONr_chiral_restr0.1420.2322
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.0212403
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02424
LS refinement shellResolution: 1.9→2.003 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.266 197 -
Rwork0.229 3424 -
all-3621 -
obs--98.53 %

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