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- PDB-1pxm: HUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR 3-[4... -

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Basic information

Entry
Database: PDB / ID: 1pxm
TitleHUMAN CYCLIN DEPENDENT KINASE 2 COMPLEXED WITH THE INHIBITOR 3-[4-(2,4-Dimethyl-thiazol-5-yl)-pyrimidin-2-ylamino]-phenol
ComponentsCell division protein kinase 2
KeywordsTRANSFERASE / PROTEIN KINASE / CELL CYCLE / PHOSPHORYLATION / CELL DIVISION / MITOSIS / INHIBITION / SERINE/THREONINE-PROTEIN KINASE / ATP-BINDING / 3D-STRUCTURE.
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 / Y chromosome / cyclin-dependent protein kinase activity / 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 / Y chromosome / cyclin-dependent protein kinase activity / 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 / 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 / Cajal body / 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 / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / DNA Damage/Telomere Stress Induced Senescence / potassium ion transport / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G2/M transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / Cyclin D associated events in G1 / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / transcription regulator complex / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / chromosome, telomeric region / DNA replication / protein phosphorylation / endosome / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / positive regulation of cell population proliferation / DNA-templated transcription / centrosome / positive regulation of DNA-templated transcription / magnesium ion binding / negative regulation of transcription by RNA polymerase II / signal transduction / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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 ...: / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-CK5 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.53 Å
AuthorsWang, S. / Meades, C. / Wood, G. / Osnowski, A. / Anderson, S. / Yuill, R. / Thomas, M. / Jackson, W. / Midgley, C. / Griffiths, G. ...Wang, S. / Meades, C. / Wood, G. / Osnowski, A. / Anderson, S. / Yuill, R. / Thomas, M. / Jackson, W. / Midgley, C. / Griffiths, G. / McNae, I. / Wu, S.Y. / McInnes, C. / Zheleva, D. / Walkinshaw, M.D. / Fischer, P.M.
Citation
Journal: J.Med.Chem. / Year: 2004
Title: 2-Anilino-4-(thiazol-5-yl)pyrimidine CDK inhibitors: synthesis, SAR analysis, X-ray crystallography, and biological activity.
Authors: Wang, S. / Meades, C. / Wood, G. / Osnowski, A. / Anderson, S. / Yuill, R. / Thomas, M. / Mezna, M. / Jackson, W. / Midgley, C. / Griffiths, G. / Fleming, I. / Green, S. / McNae, I. / Wu, S. ...Authors: Wang, S. / Meades, C. / Wood, G. / Osnowski, A. / Anderson, S. / Yuill, R. / Thomas, M. / Mezna, M. / Jackson, W. / Midgley, C. / Griffiths, G. / Fleming, I. / Green, S. / McNae, I. / Wu, S.Y. / McInnes, C. / Zheleva, D. / Walkinshaw, M.D. / Fischer, P.M.
#1: Journal: Structure / Year: 2003
Title: Discovery of a novel family of CDK inhibitors with the program LIDAEUS: structural basis for ligand-induced disordering of the activation loop
Authors: Wu, S.Y. / McNae, I. / Kontopidis, G. / McClue, S.J. / McInnes, C. / Stewart, K.J. / Wang, S. / Zheleva, D.I. / Marriage, H. / Lane, D.P. / Taylor, P. / Fischer, P.M. / Walkinshaw, M.D.
History
DepositionJul 4, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 13, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 16, 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
Remark 600HETEROGEN CK5 500 has alternate conformation with HOH 501,502,503,504,505,506,507,508,and 509.

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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)34,2752
Polymers33,9761
Non-polymers2981
Water2,018112
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)53.489, 71.987, 72.362
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 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 / Cell line (production host): Hi5 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P24941, Transferases; Transferring phosphorus-containing groups; Phosphotransferases with an alcohol group as acceptor
#2: Chemical ChemComp-CK5 / 3-[4-(2,4-DIMETHYL-THIAZOL-5-YL)-PYRIMIDIN-2-YLAMINO]-PHENOL


Mass: 298.363 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H14N4OS
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 112 / 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: 39.97 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: PEG 6000, NA-HEPES, pH 7.8, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SRS / Beamline: PX14.1 / Wavelength: 1.488 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.488 Å / Relative weight: 1
ReflectionResolution: 2.53→25 Å / Num. all: 9820 / Num. obs: 9784 / % possible obs: 99.9 % / Redundancy: 9.3 % / Biso Wilson estimate: 22.3 Å2 / Rmerge(I) obs: 0.117 / Net I/σ(I): 12.8
Reflection shellResolution: 2.53→2.69 Å / Rmerge(I) obs: 0.507 / Mean I/σ(I) obs: 3.38 / % possible all: 100

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Processing

Software
NameVersionClassification
CNS1refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1HCL

1hcl


Resolution: 2.53→25.07 Å / Rfactor Rfree error: 0.012 / Data cutoff high absF: 1203584.05 / Data cutoff high rms absF: 1203584.05 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0
RfactorNum. reflection% reflectionSelection details
Rfree0.28 520 5.3 %RANDOM
Rwork0.221 ---
all0.225 ---
obs0.221 9782 99.8 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 67.0624 Å2 / ksol: 0.385649 e/Å3
Displacement parametersBiso mean: 43.3 Å2
Baniso -1Baniso -2Baniso -3
1--10.14 Å20 Å20 Å2
2---9.25 Å20 Å2
3---19.39 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.41 Å0.31 Å
Luzzati d res low-5 Å
Luzzati sigma a0.42 Å0.31 Å
Refinement stepCycle: LAST / Resolution: 2.53→25.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2344 0 21 112 2477
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.007
X-RAY DIFFRACTIONc_bond_d_na
X-RAY DIFFRACTIONc_bond_d_prot
X-RAY DIFFRACTIONc_angle_d
X-RAY DIFFRACTIONc_angle_d_na
X-RAY DIFFRACTIONc_angle_d_prot
X-RAY DIFFRACTIONc_angle_deg1.3
X-RAY DIFFRACTIONc_angle_deg_na
X-RAY DIFFRACTIONc_angle_deg_prot
X-RAY DIFFRACTIONc_dihedral_angle_d22.4
X-RAY DIFFRACTIONc_dihedral_angle_d_na
X-RAY DIFFRACTIONc_dihedral_angle_d_prot
X-RAY DIFFRACTIONc_improper_angle_d0.94
X-RAY DIFFRACTIONc_improper_angle_d_na
X-RAY DIFFRACTIONc_improper_angle_d_prot
X-RAY DIFFRACTIONc_mcbond_it1.711.5
X-RAY DIFFRACTIONc_mcangle_it3.032
X-RAY DIFFRACTIONc_scbond_it2.192
X-RAY DIFFRACTIONc_scangle_it3.392.5
LS refinement shellResolution: 2.53→2.69 Å / Rfactor Rfree error: 0.031 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.328 109 6.8 %
Rwork0.26 1496 -
obs-1496 99.3 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2C8K_PAR.TXTC8K_TOP.TXT
X-RAY DIFFRACTION3WATER_REP.PARAMWATER.TOP

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