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- PDB-7bjd: Crystal structure of CHK1-10pt-mutant complex with compound 3 -

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Basic information

Entry
Database: PDB / ID: 7bjd
TitleCrystal structure of CHK1-10pt-mutant complex with compound 3
ComponentsSerine/threonine-protein kinase Chk1
KeywordsTRANSFERASE / PARKINSON'S DISEASE / LEUCINE-RICH REPEAT KINASE 2 / LRRK2 / CHECKPOINT KINASE 1 / CHK1 / MUTANT / SURROGATE / KINASE INHIBITOR / SBDD
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 / 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-TVT / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsDokurno, P. / Surgenor, A.E. / Williamson, D.S.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Design and Synthesis of Pyrrolo[2,3- d ]pyrimidine-Derived Leucine-Rich Repeat Kinase 2 (LRRK2) Inhibitors Using a Checkpoint Kinase 1 (CHK1)-Derived Crystallographic Surrogate.
Authors: Williamson, D.S. / Smith, G.P. / Mikkelsen, G.K. / Jensen, T. / Acheson-Dossang, P. / Badolo, L. / Bedford, S.T. / Chell, V. / Chen, I.J. / Dokurno, P. / Hentzer, M. / Newland, S. / Ray, S.C. ...Authors: Williamson, D.S. / Smith, G.P. / Mikkelsen, G.K. / Jensen, T. / Acheson-Dossang, P. / Badolo, L. / Bedford, S.T. / Chell, V. / Chen, I.J. / Dokurno, P. / Hentzer, M. / Newland, S. / Ray, S.C. / Shaw, T. / Surgenor, A.E. / Terry, L. / Wang, Y. / Christensen, K.V.
History
DepositionJan 14, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 7, 2021Provider: repository / Type: Initial release
Revision 1.1Aug 4, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 31, 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)34,5044
Polymers34,0941
Non-polymers4103
Water3,585199
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area220 Å2
ΔGint-15 kcal/mol
Surface area12790 Å2
MethodPISA
Unit cell
Length a, b, c (Å)44.989, 65.559, 54.336
Angle α, β, γ (deg.)90.000, 102.190, 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-TVT / 2-methyl-2-(3-methyl-4-{[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino}-1H-pyrazol-1-yl)propanenitrile / 2-methyl-2-[3-methyl-4-[[4-(methylamino)-5-(trifluoromethyl)pyrimidin-2-yl]amino]pyrazol-1-yl]propanenitrile


Mass: 339.319 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H16F3N7 / 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
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: 2.3 Å3/Da / Density % sol: 46.46 %
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 / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.97625 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Sep 25, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97625 Å / Relative weight: 1
ReflectionResolution: 1.81→43.97 Å / Num. obs: 20985 / % possible obs: 73.9 % / Redundancy: 6.9 % / CC1/2: 0.999 / Rmerge(I) obs: 0.074 / Net I/σ(I): 13.5
Reflection shellResolution: 1.81→1.94 Å / Redundancy: 6.8 % / Rmerge(I) obs: 1.31 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 1050 / CC1/2: 0.578 / % possible all: 19.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
REFMAC5.8.0258refinement
PDB_EXTRACT3.27data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5oop

5oop


Resolution: 2→25 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.95 / SU B: 3.698 / SU ML: 0.1 / SU R Cruickshank DPI: 0.1818 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.182 / ESU R Free: 0.152 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.1969 892 4.8 %RANDOM
Rwork0.1622 ---
obs0.1639 17696 88.52 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 120.74 Å2 / Biso mean: 37.141 Å2 / Biso min: 14.71 Å2
Baniso -1Baniso -2Baniso -3
1--0.43 Å2-0 Å2-0.02 Å2
2--0.25 Å2-0 Å2
3---0.18 Å2
Refinement stepCycle: final / Resolution: 2→25 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2103 0 26 199 2328
Biso mean--40.86 45.41 -
Num. residues----263
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0132189
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172039
X-RAY DIFFRACTIONr_angle_refined_deg1.621.6432978
X-RAY DIFFRACTIONr_angle_other_deg1.3551.5784726
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.8565265
X-RAY DIFFRACTIONr_dihedral_angle_2_deg32.8922.719114
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.32315377
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.6841513
X-RAY DIFFRACTIONr_chiral_restr0.0770.2279
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.022421
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02445
LS refinement shellResolution: 2→2.107 Å / Rfactor Rfree error: 0 / Total num. of bins used: 10
RfactorNum. reflection% reflection
Rfree0.276 71 -
Rwork0.262 1272 -
all-1343 -
obs--44.13 %

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