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- PDB-4bgh: Crystal Structure of CDK2 in complex with pan-CDK Inhibitor -

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Basic information

Entry
Database: PDB / ID: 4bgh
TitleCrystal Structure of CDK2 in complex with pan-CDK Inhibitor
ComponentsCYCLIN-DEPENDENT KINASE 2
KeywordsTRANSFERASE
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 / telomere maintenance in response to DNA damage / centrosome duplication / G0 and Early G1 / Telomere Extension By Telomerase / cellular response to nitric oxide / Activation of the pre-replicative complex / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Activation of ATR in response to replication stress / Cyclin E associated events during G1/S transition / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / mitotic G1 DNA damage checkpoint signaling / Cyclin A:Cdk2-associated events at S phase entry / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / regulation of mitotic cell cycle / post-translational protein modification / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / meiotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / G1/S transition of mitotic cell cycle / 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) / peptidyl-serine phosphorylation / regulation of gene expression / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / endosome / chromatin remodeling / protein phosphorylation / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / centrosome / 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 ...: / 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-3I6 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 1.95 Å
AuthorsLuecking, U. / Jautelat, R. / Krueger, M. / Brumby, T. / Lienau, P. / Schaefer, M. / Briem, H. / Schulze, J. / Hillisch, A. / Reichel, A. / Siemeister, G.
CitationJournal: Chemmedchem / Year: 2013
Title: The Lab Oddity Prevails: Discovery of Pan-Cdk Inhibitor (R)- S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-Hydroxy-1-Methylpropyl]Oxy}-5-(Trifluoromethyl)Pyrimidin-2-Yl]Amino}Phenyl)Sulfoximide (Bay ...Title: The Lab Oddity Prevails: Discovery of Pan-Cdk Inhibitor (R)- S-Cyclopropyl-S-(4-{[4-{[(1R,2R)-2-Hydroxy-1-Methylpropyl]Oxy}-5-(Trifluoromethyl)Pyrimidin-2-Yl]Amino}Phenyl)Sulfoximide (Bay 1000394) for the Treatment of Cancer.
Authors: Lucking, U. / Jautelat, R. / Kruger, M. / Brumby, T. / Lienau, P. / Schafer, M. / Briem, H. / Schulze, J. / Hillisch, A. / Reichel, A. / Wengner, A.M. / Siemeister, G.
History
DepositionMar 26, 2013Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 4, 2013Provider: repository / Type: Initial release
Revision 1.1May 8, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _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: CYCLIN-DEPENDENT KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3792
Polymers33,9761
Non-polymers4021
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)53.076, 71.795, 72.196
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CYCLIN-DEPENDENT KINASE 2 / CELL DIVISION PROTEIN KINASE 2 / P33 PROTEIN KINASE


Mass: 33976.488 Da / Num. of mol.: 1 / Fragment: CATALYTIC DOMAIN, RESIDUES 1-298
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P24941, cyclin-dependent kinase
#2: Chemical ChemComp-3I6 / 4-((5-BROMO-4-(PROP-2-YN-1-YLAMINO)PYRIMIDIN-2-YL)AMINO)BENZENESULFONAMIDE


Mass: 402.267 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H16BrN5O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 2.03 Å3/Da / Density % sol: 39.44 % / Description: NONE

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Type: ESRF / Wavelength: 0.802
DetectorType: ADSC CCD / Detector: CCD / Date: Apr 8, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.802 Å / Relative weight: 1
ReflectionResolution: 1.95→25 Å / Num. obs: 20345 / % possible obs: 98.1 % / Observed criterion σ(I): 2 / Redundancy: 3.5 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 12.4

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Processing

Software
NameVersionClassification
REFMAC5.7.0032refinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: OTHER
Starting model: NONE

Resolution: 1.95→24.92 Å / Cor.coef. Fo:Fc: 0.953 / Cor.coef. Fo:Fc free: 0.928 / SU B: 8.507 / SU ML: 0.116 / Cross valid method: THROUGHOUT / ESU R: 0.184 / ESU R Free: 0.17 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.24616 1047 5.2 %RANDOM
Rwork0.19312 ---
obs0.19583 19278 98.03 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 37.099 Å2
Baniso -1Baniso -2Baniso -3
1--0.76 Å20 Å20 Å2
2---2.71 Å20 Å2
3---3.48 Å2
Refinement stepCycle: LAST / Resolution: 1.95→24.92 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2212 0 23 52 2287
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0192299
X-RAY DIFFRACTIONr_bond_other_d0.0010.022263
X-RAY DIFFRACTIONr_angle_refined_deg1.9681.9853117
X-RAY DIFFRACTIONr_angle_other_deg0.9773.0015198
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.795272
X-RAY DIFFRACTIONr_dihedral_angle_2_deg46.19923.33396
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.25815402
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.8421513
X-RAY DIFFRACTIONr_chiral_restr0.1330.2350
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0212504
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02518
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.7792.7191097
X-RAY DIFFRACTIONr_mcbond_other2.782.721096
X-RAY DIFFRACTIONr_mcangle_it4.264.0541366
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.7793.2241202
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.949→2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.318 70 -
Rwork0.256 1263 -
obs--90.25 %
Refinement TLS params.Method: refined / Origin x: 10.9329 Å / Origin y: 3.8833 Å / Origin z: 13.0025 Å
111213212223313233
T0.0541 Å20.0012 Å2-0.0167 Å2-0.0692 Å20.0116 Å2--0.0248 Å2
L0.3854 °20.2151 °2-0.2351 °2-0.9734 °2-0.0519 °2--0.1614 °2
S0.0411 Å °-0.0344 Å °-0.0153 Å °-0.0033 Å °-0.0407 Å °-0.0288 Å °-0.0153 Å °0.039 Å °-0.0004 Å °

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