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- PDB-5l2s: The X-ray co-crystal structure of human CDK6 and Abemaciclib. -

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Basic information

Entry
Database: PDB / ID: 5l2s
TitleThe X-ray co-crystal structure of human CDK6 and Abemaciclib.
ComponentsCyclin-dependent kinase 6
KeywordsTransferase/Transferase Inhibitor / cyclin-dependent kinase / kinase inhibitor / kinase selectivity / Transferase-Transferase Inhibitor complex
Function / homology
Function and homology information


cyclin D2-CDK6 complex / cell dedifferentiation / Drug-mediated inhibition of CDK4/CDK6 activity / 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 / FBXO family protein binding / lateral ventricle development / negative regulation of myeloid cell differentiation / type B pancreatic cell development / negative regulation of monocyte differentiation ...cyclin D2-CDK6 complex / cell dedifferentiation / Drug-mediated inhibition of CDK4/CDK6 activity / 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 / FBXO family protein binding / lateral ventricle development / negative regulation of myeloid cell differentiation / type B pancreatic cell development / negative regulation of monocyte differentiation / astrocyte development / dentate gyrus development / gliogenesis / regulation of cell motility / Regulation of RUNX1 Expression and Activity / regulation of hematopoietic stem cell differentiation / 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 differentiation / negative regulation of cell cycle / cyclin-dependent protein kinase holoenzyme complex / hematopoietic stem cell differentiation / negative regulation of osteoblast differentiation / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / Notch signaling pathway / ruffle / regulation of G2/M transition of mitotic cell cycle / cyclin binding / response to organic substance / G1/S transition of mitotic cell cycle / response to virus / regulation of erythrocyte differentiation / Oncogene Induced Senescence / Cyclin D associated events in G1 / positive regulation of fibroblast proliferation / negative regulation of epithelial cell proliferation / T cell differentiation in thymus / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / Oxidative Stress Induced Senescence / regulation of cell cycle / cell division / negative regulation of cell population proliferation / protein phosphorylation / protein serine kinase activity / centrosome / positive regulation of gene expression / negative regulation of transcription by RNA polymerase II / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Cyclin-dependent kinase 6 / 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 ...Cyclin-dependent kinase 6 / 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-6ZV / Cyclin-dependent kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 2.27 Å
AuthorsChen, P. / Ferre, R.A. / Deihl, W. / Yu, X. / He, Y.-A.
CitationJournal: Mol.Cancer Ther. / Year: 2016
Title: Spectrum and Degree of CDK Drug Interactions Predicts Clinical Performance.
Authors: Chen, P. / Lee, N.V. / Hu, W. / Xu, M. / Ferre, R.A. / Lam, H. / Bergqvist, S. / Solowiej, J. / Diehl, W. / He, Y.A. / Yu, X. / Nagata, A. / VanArsdale, T. / Murray, B.W.
History
DepositionAug 2, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2016Group: Database references
Revision 1.2Mar 6, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / entity / pdbx_entity_nonpoly / pdbx_struct_oper_list
Item: _chem_comp.name / _database_2.pdbx_DOI ..._chem_comp.name / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _entity.pdbx_description / _pdbx_entity_nonpoly.name / _pdbx_struct_oper_list.symmetry_operation

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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)35,5262
Polymers35,0191
Non-polymers5071
Water37821
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)102.170, 102.170, 59.830
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: UNP residues 1-301
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK6, CDKN6 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q00534, cyclin-dependent kinase
#2: Chemical ChemComp-6ZV / N-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl}-5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]py rimidin-2-amine / Abemaciclib / Abemaciclib


Mass: 506.593 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32F2N8 / Comment: medication, inhibitor*YM
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 21 / 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: 2.28 Å3/Da / Density % sol: 46.13 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion, sitting drop
Details: 1:1 (protein to well buffer) with well buffer containing: 0.1 M MES pH 6.0, 70 - 80 mM NH4NO3, 10 - 15% polyethyleneglycol 3350

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Data collection

DiffractionMean temperature: 98.15 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Aug 8, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.27→72 Å / Num. obs: 14466 / % possible obs: 100 % / Redundancy: 6.24 % / Biso Wilson estimate: 59.6 Å2 / Net I/σ(I): 26.2

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
autoXDSdata processing
BUSTERphasing
Aimlessdata scaling
RefinementResolution: 2.27→72 Å / Cor.coef. Fo:Fc: 0.9369 / Cor.coef. Fo:Fc free: 0.9188 / SU R Cruickshank DPI: 0.288 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.268 / SU Rfree Blow DPI: 0.21 / SU Rfree Cruickshank DPI: 0.218
RfactorNum. reflection% reflectionSelection details
Rfree0.2488 1033 7.18 %RANDOM
Rwork0.206 ---
obs0.209 14386 99.95 %-
Displacement parametersBiso mean: 58.77 Å2
Baniso -1Baniso -2Baniso -3
1--6.6455 Å20 Å20 Å2
2---6.6455 Å20 Å2
3---13.2909 Å2
Refine analyzeLuzzati coordinate error obs: 0.317 Å
Refinement stepCycle: 1 / Resolution: 2.27→72 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2091 0 37 21 2149
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0092210HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.073023HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d756SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes49HARMONIC2
X-RAY DIFFRACTIONt_gen_planes348HARMONIC5
X-RAY DIFFRACTIONt_it2210HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.72
X-RAY DIFFRACTIONt_other_torsion19.94
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion272SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2479SEMIHARMONIC4
LS refinement shellResolution: 2.27→2.45 Å / Total num. of bins used: 7
RfactorNum. reflection% reflection
Rfree0.2658 222 7.5 %
Rwork0.2242 2738 -
all0.2271 2960 -
obs--99.95 %

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