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- PDB-2c6m: Crystal structure of the human CDK2 complexed with the triazolopy... -

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Basic information

Entry
Database: PDB / ID: 2c6m
TitleCrystal structure of the human CDK2 complexed with the triazolopyrimidine inhibitor
ComponentsCELL DIVISION PROTEIN KINASE 2
KeywordsTRANSFERASE / SERINE/THREONINE PROTEIN KINASE / CDK2 / ATP-BINDING / CELL CYCLE / MITOSIS / PHOSPHORYLATION / TRIAZOLOPYRIMIDINE INHIBITOR / CELL DIVISION / KINASE / POLYMORPHISM / NUCLEOTIDE-BINDING
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-DT5 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsRichardson, C.M. / Dokurno, P. / Murray, J.B. / Surgenor, A.E.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2006
Title: Triazolo[1,5-A]Pyrimidines as Novel Cdk2 Inhibitors: Protein Structure-Guided Design and Sar.
Authors: Richardson, C.M. / Williamson, D.S. / Parratt, M.J. / Borgognoni, J. / Cansfield, A.D. / Dokurno, P. / Francis, G.L. / Howes, R. / Moore, J.D. / Murray, J.B. / Robertson, A. / Surgenor, A.E. / Torrance, C.J.
History
DepositionNov 10, 2005Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 7, 2005Provider: repository / Type: Initial release
Revision 1.1Sep 16, 2015Group: Derived calculations / Non-polymer description ...Derived calculations / Non-polymer description / Other / Source and taxonomy / Version format compliance
Revision 1.2Jan 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
Item: _exptl_crystal_grow.method / _pdbx_database_status.recvd_author_approval
Revision 1.3Apr 24, 2019Group: Data collection / Source and taxonomy / Category: entity_src_gen / Item: _entity_src_gen.pdbx_host_org_cell_line
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_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

Downloads & links

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Assembly

Deposited unit
A: CELL DIVISION PROTEIN KINASE 2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3652
Polymers33,9761
Non-polymers3881
Water4,468248
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPQS
Unit cell
Length a, b, c (Å)53.662, 71.702, 72.384
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): Sf21 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P24941, EC: 2.7.1.37
#2: Chemical ChemComp-DT5 / 4-{[5-(CYCLOHEXYLOXY)[1,2,4]TRIAZOLO[1,5-A]PYRIMIDIN-7-YL]AMINO}BENZENESULFONAMIDE


Mass: 388.444 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C17H20N6O3S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 248 / Source method: isolated from a natural source / Formula: H2O
Compound detailsINVOLVED IN THE CONTROL OF THE CELL CYCLE.

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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: 2.1 Å3/Da / Density % sol: 39.6 %
Crystal growMethod: vapor diffusion, hanging drop / pH: 7.2
Details: PEG3350, HEPES PH7.2, AMMONIUM ACETATE, VAPOR DIFFUSION HANGING DROP, ROOM TEMPERATURE, pH 7.20

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU RUH3R / Wavelength: 1.5418
DetectorType: RIGAKU MSC / Detector: IMAGE PLATE / Date: Apr 10, 2003 / Details: MIRRORS
RadiationMonochromator: MSC OSMIC BLUE / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 1.9→30 Å / Num. obs: 21538 / % possible obs: 95.2 % / Redundancy: 2.3 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 15.1
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 3.07 % / Rmerge(I) obs: 0.22 / Mean I/σ(I) obs: 2.9 / % possible all: 72.9

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Processing

Software
NameVersionClassification
REFMAC5.1.24refinement
CrystalCleardata reduction
d*TREKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1B39

1b39


Resolution: 1.9→15 Å / Cor.coef. Fo:Fc: 0.952 / Cor.coef. Fo:Fc free: 0.907 / SU B: 4.507 / SU ML: 0.132 / Cross valid method: THROUGHOUT / ESU R: 0.205 / ESU R Free: 0.195 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.27 1791 8.3 %RANDOM
Rwork0.195 ---
obs0.201 19712 95.2 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 36.2 Å2
Baniso -1Baniso -2Baniso -3
1-0.2 Å20 Å20 Å2
2---1.09 Å20 Å2
3---0.9 Å2
Refinement stepCycle: LAST / Resolution: 1.9→15 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2321 0 27 248 2596
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0222413
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5641.9513279
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9335288
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_restr0.1070.2366
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.021801
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2280.21240
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1580.2213
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1980.264
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.150.228
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.9991.51453
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it1.72622359
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.6283960
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.9924.5920
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: 1.9→1.95 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.346 95
Rwork0.274 1049

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