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- PDB-3fz1: Crystal structure of a benzthiophene inhibitor bound to human Cyc... -

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Basic information

Entry
Database: PDB / ID: 3fz1
TitleCrystal structure of a benzthiophene inhibitor bound to human Cyclin-dependent Kinase-2 (CDK-2)
ComponentsCell division protein kinase 2
KeywordsTRANSFERASE / CDK-2 / MK-2 / MK2 / MAPKAP kinase-2 / Ser/Thr kinase / cell divison kinase-2 / cyclin / benzothiophene / ATP-binding / Cell cycle / Cell division / Kinase / Mitosis / Nucleotide-binding / Phosphoprotein / Polymorphism / Serine/threonine-protein kinase
Function / homology
Function and homology information


cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / cyclin-dependent protein kinase activity / Y chromosome / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation ...cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / cyclin-dependent protein kinase activity / Y chromosome / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / X chromosome / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cyclin-dependent protein kinase holoenzyme complex / cellular response to nitric oxide / Cajal body / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Activation of ATR in response to replication stress / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / meiotic cell cycle / male germ cell nucleus / response to organic substance / G1/S transition of mitotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / Meiotic recombination / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / G2/M transition of mitotic cell cycle / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / Ras protein signal transduction / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / DNA replication / chromosome, telomeric region / endosome / chromatin remodeling / cell division / protein domain specific binding / protein phosphorylation / DNA repair / protein serine kinase activity / centrosome / protein serine/threonine kinase activity / DNA-templated transcription / positive regulation of cell population proliferation / positive regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / magnesium ion binding / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
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. ...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-B98 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsKurumbail, R.G. / Caspers, N.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2009
Title: Benzothiophene inhibitors of MK2. Part 2: improvements in kinase selectivity and cell potency.
Authors: Anderson, D.R. / Meyers, M.J. / Kurumbail, R.G. / Caspers, N. / Poda, G.I. / Long, S.A. / Pierce, B.S. / Mahoney, M.W. / Mourey, R.J. / Parikh, M.D.
History
DepositionJan 23, 2009Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 7, 2009Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
Revision 1.3Sep 6, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cell division protein kinase 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,2542
Polymers33,9761
Non-polymers2771
Water3,801211
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.717, 71.709, 72.242
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Cell division protein kinase 2 / / p33 protein kinase


Mass: 33976.488 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDK2_Human / Production host: Spodoptera frugiperda (fall armyworm) / Strain (production host): Sf21 / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-B98 / (3R)-3-(aminomethyl)-9-methoxy-1,2,3,4-tetrahydro-5H-[1]benzothieno[3,2-e][1,4]diazepin-5-one


Mass: 277.342 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H15N3O2S
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 211 / 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: 2.05 Å3/Da / Density % sol: 40.08 %
Crystal growTemperature: 291 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: CDK-1 at 2.5 mg/ml is equilibrated against a well solution containing 14% PEG 4000, 50 mM ammonium acetate, 50 mM Hepes pH 7.5, 10 mM DTT, VAPOR DIFFUSION, HANGING DROP, temperature 291K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.54 Å
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE / Date: Jan 7, 2005
RadiationMonochromator: graphite / Protocol: SINGLE WAVELENGTH / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. obs: 22384 / % possible obs: 99 % / Redundancy: 4.2 % / Rmerge(I) obs: 0.04 / Χ2: 0.988 / Net I/σ(I): 29.843
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.9-1.973.70.33421850.97198.9
1.97-2.053.90.24322300.94699.7
2.05-2.143.90.1922071.08699.5
2.14-2.2540.14322211.09199.6
2.25-2.394.10.1122211.05799.7
2.39-2.584.20.08322321.01899.5
2.58-2.844.30.06222381.02899.4
2.84-3.254.40.0422420.94399.3
3.25-4.094.50.02522750.97998.5
4.09-304.50.01723330.79796

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
REFMACrefinement
PDB_EXTRACT3.006data extraction
HKL-2000data collection
HKL-2000data reduction
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1AQ1

1aq1


Resolution: 1.9→27.66 Å / Cor.coef. Fo:Fc: 0.944 / Cor.coef. Fo:Fc free: 0.924 / WRfactor Rfree: 0.256 / WRfactor Rwork: 0.202 / Occupancy max: 1 / Occupancy min: 1 / FOM work R set: 0.831 / SU B: 3.733 / SU ML: 0.114 / SU R Cruickshank DPI: 0.193 / SU Rfree: 0.173 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.193 / ESU R Free: 0.173 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.259 1147 5.1 %RANDOM
Rwork0.21 ---
obs0.212 22346 98.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 67.16 Å2 / Biso mean: 30.062 Å2 / Biso min: 12.05 Å2
Baniso -1Baniso -2Baniso -3
1--0.07 Å20 Å20 Å2
2--0.24 Å20 Å2
3----0.16 Å2
Refine analyzeLuzzati coordinate error obs: 0.224 Å
Refinement stepCycle: LAST / Resolution: 1.9→27.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2284 0 19 211 2514
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222363
X-RAY DIFFRACTIONr_angle_refined_deg1.211.9863206
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.9985281
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.28723.3100
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.54415410
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.6841514
X-RAY DIFFRACTIONr_chiral_restr0.0760.2357
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211787
X-RAY DIFFRACTIONr_mcbond_it0.81.51423
X-RAY DIFFRACTIONr_mcangle_it1.47322308
X-RAY DIFFRACTIONr_scbond_it1.9233940
X-RAY DIFFRACTIONr_scangle_it3.154.5898
LS refinement shellResolution: 1.901→1.95 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.335 74 -
Rwork0.232 1523 -
all-1597 -
obs--97.68 %

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