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- PDB-5l2i: The X-ray co-crystal structure of human CDK6 and Palbociclib. -

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Basic information

Entry
Database: PDB / ID: 5l2i
TitleThe X-ray co-crystal structure of human CDK6 and Palbociclib.
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 / hematopoietic stem cell differentiation / cyclin-dependent protein kinase holoenzyme complex / 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 virus / regulation of erythrocyte differentiation / Oncogene Induced Senescence / G1/S transition of mitotic cell cycle / Cyclin D associated events in G1 / negative regulation of epithelial cell proliferation / positive regulation of fibroblast proliferation / T cell differentiation in thymus / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / Oxidative Stress Induced Senescence / regulation of cell cycle / negative regulation of cell population proliferation / cell division / 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-LQQ / Cyclin-dependent kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.75 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 1, 2016Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 24, 2016Provider: repository / Type: Initial release
Revision 1.1Oct 19, 2016Group: Database references
Revision 1.2Oct 4, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_struct_oper_list
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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)35,4672
Polymers35,0191
Non-polymers4481
Water0
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.749, 101.749, 60.778
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-LQQ / 6-ACETYL-8-CYCLOPENTYL-5-METHYL-2-[(5-PIPERAZIN-1-YLPYRIDIN-2-YL)AMINO]PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONE / Palbociclib / Palbociclib


Mass: 447.533 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H29N7O2 / Comment: medication, inhibitor*YM

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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: 2.25 Å3/Da / Density % sol: 45.24 %
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 6M / Detector: PIXEL / Date: Aug 19, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 8324 / % possible obs: 100 % / Redundancy: 6.8 % / Biso Wilson estimate: 100.71 Å2 / Net I/σ(I): 14.6

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Processing

Software
NameVersionClassification
BUSTER2.11.4refinement
autoXDS20151015data processing
BUSTERphasing
Aimless0.5.21data scaling
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 3NUX

3nux


Resolution: 2.75→37 Å / Cor.coef. Fo:Fc: 0.9388 / Cor.coef. Fo:Fc free: 0.8762 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 3.599 / SU Rfree Blow DPI: 0.408
RfactorNum. reflection% reflectionSelection details
Rfree0.3037 833 10.17 %RANDOM
Rwork0.2262 ---
obs0.2346 8187 99.96 %-
Displacement parametersBiso mean: 92.38 Å2
Baniso -1Baniso -2Baniso -3
1--8.0007 Å20 Å20 Å2
2---8.0007 Å20 Å2
3---16.0015 Å2
Refine analyzeLuzzati coordinate error obs: 0.489 Å
Refinement stepCycle: 1 / Resolution: 2.75→37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2085 0 33 0 2118
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.012197HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.163004HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d759SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes50HARMONIC2
X-RAY DIFFRACTIONt_gen_planes338HARMONIC5
X-RAY DIFFRACTIONt_it2197HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.59
X-RAY DIFFRACTIONt_other_torsion21.01
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion269SEMIHARMONIC5
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_contact2514SEMIHARMONIC4
LS refinement shellResolution: 2.75→3.07 Å / Total num. of bins used: 5
RfactorNum. reflection% reflection
Rfree0.3369 220 9.55 %
Rwork0.2657 2083 -
all0.2721 2303 -
obs--99.96 %

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