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- PDB-9ce4: Structure of CHK1 10-pt. mutant complex with LRRK2 indazole inhib... -

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Basic information

Entry
Database: PDB / ID: 9ce4
TitleStructure of CHK1 10-pt. mutant complex with LRRK2 indazole inhibitor compound 6
ComponentsSerine/threonine-protein kinase Chk1
KeywordsTRANSFERASE / kinase / Parkinson's disease / LRRK2
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
: / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.31 Å
AuthorsPalte, R.L. / Zebisch, M. / Henry, C. / Barker, J.J.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Discovery and Optimization of N-Heteroaryl Indazole LRRK2 Inhibitors.
Authors: Logan, K.M. / Kaplan, W. / Simov, V. / Zhou, H. / Li, D. / Torres, L. / Morriello, G.J. / Acton, J.J. / Pio, B. / Chen, Y.H. / Keylor, M.H. / Johnson, R. / Kattar, S.D. / Chau, R. / Yan, X. ...Authors: Logan, K.M. / Kaplan, W. / Simov, V. / Zhou, H. / Li, D. / Torres, L. / Morriello, G.J. / Acton, J.J. / Pio, B. / Chen, Y.H. / Keylor, M.H. / Johnson, R. / Kattar, S.D. / Chau, R. / Yan, X. / Ardolino, M. / Zarate, C. / Otte, K.M. / Palte, R.L. / Xiong, T. / McMinn, S.E. / Lin, S. / Neelamkavil, S.F. / Liu, P. / Su, J. / Hegde, L.G. / Woodhouse, J.D. / Moy, L.Y. / Ciaccio, P.J. / Piesvaux, J. / Zebisch, M. / Henry, C. / Barker, J. / Wood, H.B. / Kennedy, M.E. / DiMauro, E.F. / Fell, M.J. / Fuller, P.H.
History
DepositionJun 26, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 18, 2024Provider: repository / Type: Initial release
Revision 1.1Oct 2, 2024Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last

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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)31,7819
Polymers30,9741
Non-polymers8078
Water3,837213
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)44.896, 65.238, 53.785
Angle α, β, γ (deg.)90.00, 101.49, 90.00
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: 30973.777 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-A1AV4 / (1S,4r)-4-[(1P)-5-chloro-1-(1-methyl-1H-pyrazol-4-yl)-1H-indazol-6-yl]-1-(oxetan-3-yl)piperidin-1-ium


Mass: 372.872 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H23ClN5O / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6O2
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 213 / 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: 2.49 Å3/Da / Density % sol: 50.64 %
Crystal growTemperature: 293 K / Method: vapor diffusion / pH: 6.5
Details: 7% PEG 8000, 16% 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: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.31→52.71 Å / Num. obs: 48251 / % possible obs: 93.5 % / Redundancy: 3.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.035 / Net I/σ(I): 15
Reflection shellResolution: 1.31→1.47 Å / Rmerge(I) obs: 0.754 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2413 / CC1/2: 0.59

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
autoPROCdata reduction
autoPROCdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.31→24.9 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.935 / SU R Cruickshank DPI: 0.068 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.069 / SU Rfree Blow DPI: 0.074 / SU Rfree Cruickshank DPI: 0.074
RfactorNum. reflection% reflectionSelection details
Rfree0.221 2410 5 %RANDOM
Rwork0.182 ---
obs0.184 48243 65.2 %-
Displacement parametersBiso mean: 28.14 Å2
Baniso -1Baniso -2Baniso -3
1--0.0853 Å20 Å20.5293 Å2
2--0.0607 Å20 Å2
3---0.0246 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: 1 / Resolution: 1.31→24.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2098 0 54 213 2365
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0122295HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.043151HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d817SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes403HARMONIC5
X-RAY DIFFRACTIONt_it2244HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.49
X-RAY DIFFRACTIONt_other_torsion15.36
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion279SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2756SEMIHARMONIC4
LS refinement shellResolution: 1.31→1.42 Å
RfactorNum. reflection% reflection
Rfree0.2165 -3.63 %
Rwork0.2024 930 -
obs--6.08 %

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