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- PDB-1w8c: CO-CRYSTAL STRUCTURE OF 6-CYCLOHEXYLMETHOXY-8-ISOPROPYL-9H-PURIN-... -

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Basic information

Entry
Database: PDB / ID: 1w8c
TitleCO-CRYSTAL STRUCTURE OF 6-CYCLOHEXYLMETHOXY-8-ISOPROPYL-9H-PURIN-2- YLAMINE AND MONOMERIC CDK2
ComponentsCELL DIVISION PROTEIN KINASE 2
KeywordsTRANSFERASE / CELL CYCLE / PHOSPHORYLATION / MITOSIS / INHIBITION / CELL DIVISION
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 / Cajal body / 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 / 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 / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / 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-N69 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.05 Å
AuthorsPratt, D.J. / Endicott, J.A. / Noble, M.E.M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: 8-Substituted O6-Cyclohexylmethylguanine Cdk2 Inhibitors; Using Structure-Based Inhibitor Design to Optimise an Alternative Binding Mode.
Authors: Carbain, B. / Paterson, D.J. / Anscombe, E. / Campbell-Dexter, A. / Cano, C. / Echalier, A. / Endicott, J. / Golding, B.T. / Haggerty, K. / Hardcastle, I.R. / Jewsbury, P.J. / Newell, D.R. / ...Authors: Carbain, B. / Paterson, D.J. / Anscombe, E. / Campbell-Dexter, A. / Cano, C. / Echalier, A. / Endicott, J. / Golding, B.T. / Haggerty, K. / Hardcastle, I.R. / Jewsbury, P.J. / Newell, D.R. / Noble, M. / Roche, C. / Wang, L. / Griffin, R.J.
History
DepositionSep 20, 2004Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 30, 2006Provider: repository / Type: Initial release
Revision 1.1Dec 18, 2013Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Source and taxonomy / Structure summary / Version format compliance
Revision 1.2Jan 22, 2014Group: Database references
Revision 1.3Nov 5, 2014Group: Atomic model / Derived calculations ...Atomic model / Derived calculations / Non-polymer description / Other / Structure summary
Revision 1.4Jul 5, 2017Group: Data collection / Category: diffrn_source / Item: _diffrn_source.type
Revision 1.5Mar 6, 2019Group: Data collection / Derived calculations / Experimental preparation
Category: exptl_crystal_grow / struct_conn
Item: _exptl_crystal_grow.method / _struct_conn.pdbx_leaving_atom_flag
Revision 1.6May 1, 2024Group: 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_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
Revision 1.7Oct 16, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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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)34,3242
Polymers34,0351
Non-polymers2891
Water2,702150
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.505, 71.935, 72.091
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 / CYCLIN DEPENDENT KINASE 2 / P33 PROTEIN KINASE


Mass: 34034.527 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
#2: Chemical ChemComp-N69 / 6-(CYCLOHEXYLMETHOXY)-8-ISOPROPYL-9H-PURIN-2-AMINE / INHIBITOR OF CDK2


Mass: 289.376 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C15H23N5O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 150 / Source method: isolated from a natural source / Formula: H2O
Has protein modificationY

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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: 2.04 Å3/Da / Density % sol: 39.65 % / Description: MOLECULAR REPLACEMENT MODEL SIMILAR TO 1E1V
Crystal growMethod: vapor diffusion / pH: 7.4
Details: 50 MM AMMONIUM ACETATE, 10% PEG 3350, 25% GLYCEROL, 100 MM HEPES PH 7.4. VAPOUR DIFFUSION

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR591 / Wavelength: 1.5418
DetectorType: MAR scanner 345 mm plate / Detector: IMAGE PLATE / Date: Jun 11, 2002
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.05→25.16 Å / Num. obs: 17480 / % possible obs: 97.3 % / Observed criterion σ(I): 2 / Redundancy: 3.9 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 11.1
Reflection shellResolution: 2.05→2.15 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.1 / Mean I/σ(I) obs: 5 / % possible all: 95.3

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Processing

Software
NameVersionClassification
REFMAC5.1.19refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: UNPUBLISHED DATA

Resolution: 2.05→50.64 Å / Cor.coef. Fo:Fc: 0.927 / Cor.coef. Fo:Fc free: 0.878 / SU B: 4.418 / SU ML: 0.125 / Cross valid method: THROUGHOUT / ESU R: 0.26 / ESU R Free: 0.211 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. RESIDUES 37-43 ARE DISORDERED AND NOT MODELLED
RfactorNum. reflection% reflectionSelection details
Rfree0.256 888 5.1 %RANDOM
Rwork0.196 ---
obs0.199 16566 96.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 19.8 Å2
Baniso -1Baniso -2Baniso -3
1-0.23 Å20 Å20 Å2
2---1.2 Å20 Å2
3---0.96 Å2
Refinement stepCycle: LAST / Resolution: 2.05→50.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2345 0 21 150 2516
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.0222446
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5041.9773318
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6495289
X-RAY DIFFRACTIONr_dihedral_angle_2_deg
X-RAY DIFFRACTIONr_dihedral_angle_3_deg
X-RAY DIFFRACTIONr_dihedral_angle_4_deg
X-RAY DIFFRACTIONr_chiral_restr0.0960.2371
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021814
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2180.21156
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1570.2174
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2320.259
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1620.216
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.8751.51461
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.57922378
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.3213985
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.6824.5940
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: 2.05→2.1 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.3 60
Rwork0.217 1157

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