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- PDB-7sui: Structure of CHK1 10-pt. mutant complex with LRRK2 inhibitor 22 -

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Entry
Database: PDB / ID: 7sui
TitleStructure of CHK1 10-pt. mutant complex with LRRK2 inhibitor 22
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 / TP53 Regulates Transcription of DNA Repair Genes / Ubiquitin-Mediated Degradation of Phosphorylated Cdc25A / 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-L80 / Serine/threonine-protein kinase Chk1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.119 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 2.0Mar 9, 2022Group: Atomic model / Author supporting evidence ...Atomic model / Author supporting evidence / Data collection / Derived calculations / Non-polymer description / Structure summary
Category: atom_site / chem_comp ...atom_site / chem_comp / entity / pdbx_entity_instance_feature / pdbx_entity_nonpoly / pdbx_nonpoly_scheme
Item: _atom_site.B_iso_or_equiv / _atom_site.Cartn_x ..._atom_site.B_iso_or_equiv / _atom_site.Cartn_x / _atom_site.Cartn_y / _atom_site.Cartn_z / _atom_site.auth_atom_id / _atom_site.auth_comp_id / _atom_site.label_atom_id / _atom_site.label_comp_id / _atom_site.occupancy / _atom_site.type_symbol / _chem_comp.formula / _chem_comp.formula_weight / _chem_comp.id / _chem_comp.mon_nstd_flag / _chem_comp.name / _chem_comp.type / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_instance_feature.auth_comp_id / _pdbx_entity_instance_feature.comp_id / _pdbx_entity_nonpoly.comp_id / _pdbx_entity_nonpoly.name / _pdbx_nonpoly_scheme.mon_id / _pdbx_nonpoly_scheme.pdb_mon_id
Revision 2.1Oct 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)34,6382
Polymers34,0941
Non-polymers5431
Water1,78399
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)45.091, 65.882, 54.923
Angle α, β, γ (deg.)90.000, 102.520, 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-L80 / (3R,4R)-4-{(3S,4S)-4-[6-chloro-2-({5-chloro-1-[(1R)-2,2-difluorocyclopropyl]-1H-pyrazol-4-yl}amino)quinazolin-7-yl]-3-fluoropiperidin-1-yl}oxolan-3-ol


Mass: 543.369 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H23Cl2F3N6O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 99 / 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: 2.34 Å3/Da / Density % sol: 47.34 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 11% PEG 8000, 15-20% ethylene glycol, 0.1 M MES (pH 6.5), 5% 6-aminohexanoic acid
PH range: 6.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 18-ID / Wavelength: 1 Å
DetectorType: DECTRIS EIGER2 X 9M / Detector: PIXEL / Date: Nov 20, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.119→53.617 Å / Num. obs: 12552 / % possible obs: 87.8 % / Redundancy: 3.5 % / CC1/2: 0.998 / Net I/σ(I): 7.2
Reflection shellResolution: 2.119→2.295 Å / Mean I/σ(I) obs: 1.4 / Num. unique obs: 2270 / CC1/2: 0.668

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Processing

Software
NameVersionClassification
BUSTER2.11.7 (20-MAY-2020)refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
autoPROCdata scaling
autoBUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 7SUF

7suf


Resolution: 2.119→53.617 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.908 / SU R Cruickshank DPI: 0.38 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.371 / SU Rfree Blow DPI: 0.252 / SU Rfree Cruickshank DPI: 0.255
Details: HYDROGENS WERE FULLY REFINED WITH ZERO OCCUPANCY AT NUCLEAR POSITION. REFINEMENT NOTES. NUMBER OF REFINEMENT NOTES : 1 NOTE 1 : IDEAL-DIST CONTACT TERM CONTACT SETUP. ALL ATOMS HAVE CCP4 ATOM TYPE FROM LIBRARY
RfactorNum. reflection% reflectionSelection details
Rfree0.2525 609 4.85 %RANDOM
Rwork0.1953 ---
obs0.198 12552 69.9 %-
Displacement parametersBiso max: 107.97 Å2 / Biso mean: 48.4 Å2 / Biso min: 17.4 Å2
Baniso -1Baniso -2Baniso -3
1-0.7378 Å20 Å2-0.133 Å2
2---1.5913 Å20 Å2
3---0.8535 Å2
Refine analyzeLuzzati coordinate error obs: 0.33 Å
Refinement stepCycle: final / Resolution: 2.119→53.617 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2131 0 36 99 2266
Biso mean--53.6 41.8 -
Num. residues----262
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d796SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes393HARMONIC5
X-RAY DIFFRACTIONt_it2224HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
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_contact1680SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d2247HARMONIC20.008
X-RAY DIFFRACTIONt_angle_deg3074HARMONIC20.93
X-RAY DIFFRACTIONt_omega_torsion2.82
X-RAY DIFFRACTIONt_other_torsion17.82
LS refinement shellResolution: 2.12→2.26 Å / Rfactor Rfree error: 0 / Total num. of bins used: 31
RfactorNum. reflection% reflection
Rfree0.2024 20 4.77 %
Rwork0.1872 399 -
all0.1878 419 -
obs--13.15 %

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