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- PDB-5oq6: Structure of CHK1 12-pt. mutant complex with aminopyrimido-benzod... -

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Basic information

Entry
Database: PDB / ID: 5oq6
TitleStructure of CHK1 12-pt. mutant complex with aminopyrimido-benzodiazepinone 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 / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / nucleus organization / inner cell mass cell proliferation / negative regulation of gene expression, epigenetic ...negative regulation of G0 to G1 transition / apoptotic process involved in development / histone H3T11 kinase activity / negative regulation of DNA biosynthetic process / negative regulation of mitotic nuclear division / mitotic G2/M transition checkpoint / regulation of mitotic centrosome separation / nucleus organization / inner cell mass cell proliferation / negative regulation of gene expression, epigenetic / regulation of double-strand break repair via homologous recombination / 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 / Activation of ATR in response to replication stress / positive regulation of cell cycle / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / signal transduction in response to DNA damage / replication fork / regulation of signal transduction by p53 class mediator / DNA damage checkpoint signaling / condensed nuclear chromosome / Ubiquitin Mediated Degradation of Phosphorylated Cdc25A / TP53 Regulates Transcription of DNA Repair Genes / peptidyl-threonine phosphorylation / G2/M DNA damage checkpoint / Signaling by SCF-KIT / 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 / intracellular signal transduction / chromatin remodeling / protein domain specific binding / protein phosphorylation / DNA repair / protein serine kinase activity / intracellular membrane-bounded organelle / centrosome / protein serine/threonine kinase activity / apoptotic process / DNA damage response / chromatin / 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-4K4 / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.95 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 10, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,7003
Polymers34,0941
Non-polymers6062
Water2,972165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area150 Å2
ΔGint-10 kcal/mol
Surface area12650 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.000, 66.160, 54.980
Angle α, β, γ (deg.)90.000, 101.840, 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: A19S, Y20F, 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-4K4 / 2-[(2-methoxy-4-{[4-(4-methylpiperazin-1-yl)piperidin-1-yl]carbonyl}phenyl)amino]-5,11-dimethyl-5,11-dihydro-6H-pyrimido[4,5-b][1,4]benzodiazepin-6-one


Mass: 570.685 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H38N8O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 165 / 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: 2.35 Å3/Da / Density % sol: 47.65 %
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: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Sep 20, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.91→44.04 Å / Num. obs: 24224 / % possible obs: 98.5 % / Redundancy: 2.9 % / CC1/2: 0.998 / Rmerge(I) obs: 0.051 / Rpim(I) all: 0.036 / Rrim(I) all: 0.063 / Net I/σ(I): 13.7 / Num. measured all: 70334 / Scaling rejects: 0
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
1.91-1.962.60.55517770.7730.4130.69598.2
8.54-44.042.70.0182690.9990.0120.02289.6

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Processing

Software
NameVersionClassification
Aimless0.1.16data scaling
REFMAC5.8.0158refinement
PDB_EXTRACT3.22data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5OOT

5oot


Resolution: 1.95→30 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.959 / SU B: 3.97 / SU ML: 0.105 / SU R Cruickshank DPI: 0.1345 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.134 / ESU R Free: 0.124
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1918 1164 5.1 %RANDOM
Rwork0.1578 ---
obs0.1597 21610 98.48 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 117.91 Å2 / Biso mean: 40.027 Å2 / Biso min: 16.98 Å2
Baniso -1Baniso -2Baniso -3
1--2.47 Å20 Å2-1.05 Å2
2---0.79 Å2-0 Å2
3---3.4 Å2
Refinement stepCycle: final / Resolution: 1.95→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2071 0 43 165 2279
Biso mean--47.46 44.84 -
Num. residues----257
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0190.0192167
X-RAY DIFFRACTIONr_bond_other_d0.0020.022026
X-RAY DIFFRACTIONr_angle_refined_deg1.9491.9852941
X-RAY DIFFRACTIONr_angle_other_deg1.1233.0024652
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6845255
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.96324.3100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.41715375
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.2861513
X-RAY DIFFRACTIONr_chiral_restr0.130.2315
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212368
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02422
LS refinement shellResolution: 1.95→2.055 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.265 170 -
Rwork0.269 3146 -
all-3316 -
obs--99.04 %

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