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- PDB-4aua: Liganded X-ray crystal structure of cyclin dependent kinase 6 (CDK6) -

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Basic information

Entry
Database: PDB / ID: 4aua
TitleLiganded X-ray crystal structure of cyclin dependent kinase 6 (CDK6)
ComponentsCYCLIN-DEPENDENT KINASE 6
KeywordsTRANSFERASE
Function / homology
Function and homology information


cyclin D2-CDK6 complex / cell dedifferentiation / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 / Drug-mediated inhibition of CDK4/CDK6 activity / FBXO family protein binding / lateral ventricle development / negative regulation of monocyte differentiation / negative regulation of myeloid cell differentiation / type B pancreatic cell development ...cyclin D2-CDK6 complex / cell dedifferentiation / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 and CDK6 / Drug-mediated inhibition of CDK4/CDK6 activity / FBXO family protein binding / lateral ventricle development / negative regulation of monocyte differentiation / negative regulation of myeloid cell differentiation / type B pancreatic cell development / astrocyte development / dentate gyrus development / regulation of cell motility / gliogenesis / Regulation of RUNX1 Expression and Activity / positive regulation of cell-matrix adhesion / generation of neurons / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / negative regulation of cellular senescence / negative regulation of cell cycle / hemopoiesis / negative regulation of cell differentiation / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / negative regulation of osteoblast differentiation / cyclin-dependent protein kinase holoenzyme complex / ruffle / cyclin binding / G1/S transition of mitotic cell cycle / regulation of erythrocyte differentiation / negative regulation of epithelial cell proliferation / response to virus / Oncogene Induced Senescence / G2/M transition of mitotic cell cycle / positive regulation of fibroblast proliferation / Cyclin D associated events in G1 / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / regulation of cell cycle / negative regulation of cell population proliferation / protein serine kinase activity / cell division / centrosome / DNA damage response / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Cyclin-dependent kinase 6 / : / 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 ...Cyclin-dependent kinase 6 / : / 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
1H-benzimidazol-2-yl(1H-pyrrol-2-yl)methanone / Cyclin-dependent kinase 6
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.31 Å
AuthorsCho, Y.S. / Angove, H. / Brain, C. / Chen, C.H.T. / Cheng, R. / Chopra, R. / Chung, K. / Congreve, M. / Dagostin, C. / Davis, D. ...Cho, Y.S. / Angove, H. / Brain, C. / Chen, C.H.T. / Cheng, R. / Chopra, R. / Chung, K. / Congreve, M. / Dagostin, C. / Davis, D. / Feltell, R. / Giraldes, J. / Hiscock, S. / Kim, S. / Kovats, S. / Lagu, B. / Lewry, K. / Loo, A. / Lu, Y. / Luzzio, M. / Maniara, W. / Mcmenamin, R. / Mortenson, P. / Benning, R. / O'Reilly, M. / Rees, D. / Shen, J. / Smith, T. / Wang, Y. / Williams, G. / Woolford, A. / Wrona, W. / Xu, M. / Yang, F. / Howard, S.
CitationJournal: ACS Med Chem Lett / Year: 2012
Title: Fragment-Based Discovery of 7-Azabenzimidazoles as Potent, Highly Selective, and Orally Active CDK4/6 Inhibitors.
Authors: Cho, Y.S. / Angove, H. / Brain, C. / Chen, C.H. / Cheng, H. / Cheng, R. / Chopra, R. / Chung, K. / Congreve, M. / Dagostin, C. / Davis, D.J. / Feltell, R. / Giraldes, J. / Hiscock, S.D. / ...Authors: Cho, Y.S. / Angove, H. / Brain, C. / Chen, C.H. / Cheng, H. / Cheng, R. / Chopra, R. / Chung, K. / Congreve, M. / Dagostin, C. / Davis, D.J. / Feltell, R. / Giraldes, J. / Hiscock, S.D. / Kim, S. / Kovats, S. / Lagu, B. / Lewry, K. / Loo, A. / Lu, Y. / Luzzio, M. / Maniara, W. / McMenamin, R. / Mortenson, P.N. / Benning, R. / O'Reilly, M. / Rees, D.C. / Shen, J. / Smith, T. / Wang, Y. / Williams, G. / Woolford, A.J. / Wrona, W. / Xu, M. / Yang, F. / Howard, S.
History
DepositionMay 15, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 6, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2014Group: Database references
Revision 1.2Feb 7, 2018Group: Database references / Structure summary / Category: audit_author / citation / citation_author
Item: _audit_author.name / _citation.journal_abbrev ..._audit_author.name / _citation.journal_abbrev / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title
Revision 1.3Apr 3, 2019Group: Data collection / Experimental preparation / Category: exptl_crystal_grow / Item: _exptl_crystal_grow.temp
Revision 1.4May 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 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,2302
Polymers35,0191
Non-polymers2111
Water1,54986
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)100.734, 100.734, 60.300
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number79
Space group name H-MI4

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Components

#1: Protein CYCLIN-DEPENDENT KINASE 6 / CELL DIVISION PROTEIN KINASE 6 / SERINE/THREONINE-PROTEIN KINASE PLSTIRE


Mass: 35019.215 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 1-301
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q00534, cyclin-dependent kinase
#2: Chemical ChemComp-4AU / 1H-benzimidazol-2-yl(1H-pyrrol-2-yl)methanone


Mass: 211.219 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C12H9N3O
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 86 / 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: 2.18 Å3/Da / Density % sol: 43.68 % / Description: NONE
Crystal growTemperature: 287 K / pH: 5.7
Details: 5MG/ML 0.1 M MES/NAOH PH 5.7,, 4.5% W/V PEG 3350, 25 MM SODIUM NITRATE, 10% V/V GLYCEROL, 10 DEGREES CELSIUS

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.9611
DetectorType: ADSC QUANTUM 315r / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9611 Å / Relative weight: 1
ReflectionResolution: 2.3→71.23 Å / Num. obs: 13277 / % possible obs: 98 % / Observed criterion σ(I): 1 / Redundancy: 3.6 % / Rmerge(I) obs: 0.04 / Net I/σ(I): 17.4
Reflection shellResolution: 2.3→2.36 Å / Redundancy: 3.8 % / Rmerge(I) obs: 0.37 / Mean I/σ(I) obs: 3.9 / % possible all: 98.6

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Processing

Software
NameVersionClassification
REFMAC5.2.0019Grefinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.31→71.23 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.911 / SU B: 9.961 / SU ML: 0.238 / Cross valid method: THROUGHOUT / ESU R: 0.369 / ESU R Free: 0.274 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.27734 680 5.2 %RANDOM
Rwork0.20668 ---
obs0.21033 12395 97.9 %-
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: 46.949 Å2
Baniso -1Baniso -2Baniso -3
1-2.42 Å20 Å20 Å2
2--2.42 Å20 Å2
3----4.83 Å2
Refinement stepCycle: LAST / Resolution: 2.31→71.23 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2048 0 16 86 2150
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0222110
X-RAY DIFFRACTIONr_bond_other_d0.0010.021466
X-RAY DIFFRACTIONr_angle_refined_deg1.3541.9672853
X-RAY DIFFRACTIONr_angle_other_deg0.9482.9933557
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2435251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg34.83823.46998
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.91615366
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1021516
X-RAY DIFFRACTIONr_chiral_restr0.0790.2319
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.022294
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02440
X-RAY DIFFRACTIONr_nbd_refined0.2110.2485
X-RAY DIFFRACTIONr_nbd_other0.2010.21521
X-RAY DIFFRACTIONr_nbtor_refined0.180.21025
X-RAY DIFFRACTIONr_nbtor_other0.090.21085
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1520.231
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.0250.21
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.130.211
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2490.229
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0590.23
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it0.03751274
X-RAY DIFFRACTIONr_mcbond_other0.0135512
X-RAY DIFFRACTIONr_mcangle_it0.05762060
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it0.0476836
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it0.0637.5793
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: 2.311→2.371 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.428 60 -
Rwork0.292 884 -
obs--98.64 %

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