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- PDB-2clx: 4-Arylazo-3,5-diamino-1H-pyrazole CDK Inhibitors: SAR Study, Crys... -

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Basic information

Entry
Database: PDB / ID: 2clx
Title4-Arylazo-3,5-diamino-1H-pyrazole CDK Inhibitors: SAR Study, Crystal Structure in Complex with CDK2, Selectivity, and Cellular Effects
ComponentsCELL DIVISION PROTEIN KINASE 2
KeywordsTRANSFERASE / SERINE/THREONINE- PROTEIN KINASE / PHOSPHORYLATION / NUCLEOTIDE-BINDING / CDK2 / KINASE / MITOSIS / CELL CYCLE / ATP-BINDING / POLYMORPHISM / CELL DIVISION / 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 / cyclin-dependent protein kinase activity / G2 Phase / 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 / cyclin-dependent protein kinase activity / G2 Phase / 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 / Telomere Extension By Telomerase / G0 and Early G1 / 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 / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / regulation of mitotic cell cycle / cellular response to nitric oxide / 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 / G1/S transition of mitotic cell cycle / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / G2/M transition of mitotic cell cycle / 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 / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / endosome / chromatin remodeling / protein domain specific binding / protein phosphorylation / cell division / protein serine/threonine kinase activity / protein serine kinase activity / DNA repair / DNA-templated transcription / centrosome / 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
: / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site ...: / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-F18 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsKrystof, V. / Cankar, P. / Frysova, I. / Slouka, J. / Kontopidis, G. / Dzubak, P. / Hajduch, M. / Deazevedo, W.F. / Paprskarova, M. / Orsag, M. ...Krystof, V. / Cankar, P. / Frysova, I. / Slouka, J. / Kontopidis, G. / Dzubak, P. / Hajduch, M. / Deazevedo, W.F. / Paprskarova, M. / Orsag, M. / Rolcik, J. / Latr, A. / Fischer, P.M. / Strnad, M.
CitationJournal: J.Med.Chem. / Year: 2006
Title: 4-Arylazo-3,5-Diamino-1H-Pyrazole Cdk Inhibitors: Sar Study, Crystal Structure in Complex with Cdk2, Selectivity, and Cellular Effects
Authors: Krystof, V. / Cankar, P. / Frysova, I. / Slouka, J. / Kontopidis, G. / Dzubak, P. / Hajduch, M. / De Azevedo Junior, W.F. / Paprskarova, M. / Orsag, M. / Rolcik, J. / Latr, A. / Fischer, P.M. / Strnad, M.
History
DepositionMay 2, 2006Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 1, 2006Provider: repository / Type: Initial release
Revision 1.1May 8, 2011Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Jan 30, 2019Group: Data collection / Experimental preparation / Other
Category: database_PDB_rev / database_PDB_rev_record ...database_PDB_rev / database_PDB_rev_record / exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_biol
Item: _exptl_crystal_grow.method / _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval
Revision 1.4Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn
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_conn.pdbx_leaving_atom_flag

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CELL DIVISION PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1952
Polymers33,9761
Non-polymers2181
Water4,558253
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.370, 70.750, 72.180
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) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P24941, EC: 2.7.1.37, cyclin-dependent kinase
#2: Chemical ChemComp-F18 / 4-[(E)-(3,5-DIAMINO-1H-PYRAZOL-4-YL)DIAZENYL]PHENOL / CAN508


Mass: 218.215 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C9H10N6O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 253 / 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: 1.84 Å3/Da / Density % sol: 32.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.8
Details: 10% PEG 3350, NAF, PH 7.0, VAPOUR DIFFUSION, HANGING DROP, TEMPERATURE 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-D / Wavelength: 1.5418
DetectorType: RIGAKU RAXIS IV / Detector: IMAGE PLATE / Date: Dec 1, 2004 / Details: MIRRORS
RadiationMonochromator: NI FILTER / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.8→29.9 Å / Num. obs: 25793 / % possible obs: 99.3 % / Observed criterion σ(I): 2.8 / Redundancy: 3.43 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 16.9
Reflection shellResolution: 1.8→1.86 Å / Redundancy: 2.67 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 2.8 / % possible all: 97.5

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Processing

Software
NameVersionClassification
REFMAC5.2.0005refinement
d*TREKdata reduction
d*TREKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 2C5Y

2c5y


Resolution: 1.8→29 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.945 / SU B: 3.477 / SU ML: 0.108 / Cross valid method: THROUGHOUT / ESU R: 0.139 / ESU R Free: 0.137 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.231 826 3.2 %RANDOM
Rwork0.178 ---
obs0.18 24966 99.3 %-
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: 36.23 Å2
Baniso -1Baniso -2Baniso -3
1-0.45 Å20 Å20 Å2
2--0.44 Å20 Å2
3----0.88 Å2
Refinement stepCycle: LAST / Resolution: 1.8→29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2357 0 16 253 2626
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222447
X-RAY DIFFRACTIONr_bond_other_d0.0010.022297
X-RAY DIFFRACTIONr_angle_refined_deg1.9941.9843316
X-RAY DIFFRACTIONr_angle_other_deg1.26635339
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.3425291
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.00623.01103
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.77515434
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.5521516
X-RAY DIFFRACTIONr_chiral_restr0.1360.2371
X-RAY DIFFRACTIONr_gen_planes_refined0.0150.022636
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02499
X-RAY DIFFRACTIONr_nbd_refined0.2950.3754
X-RAY DIFFRACTIONr_nbd_other0.2560.32664
X-RAY DIFFRACTIONr_nbtor_refined0.1970.51236
X-RAY DIFFRACTIONr_nbtor_other0.1020.51395
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2930.5347
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2670.321
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2840.369
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2940.541
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.6131.51878
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.25622387
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it6.46931134
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it8.3884.5929
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: 1.8→1.85 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.304 45
Rwork0.26 1776

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