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- PDB-2f2c: X-ray structure of human CDK6-Vcyclinwith the inhibitor aminopurv... -

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Basic information

Entry
Database: PDB / ID: 2f2c
TitleX-ray structure of human CDK6-Vcyclinwith the inhibitor aminopurvalanol
Components
  • Cell division protein kinase 6
  • Cyclin homolog
KeywordsCELL CYCLE/TRANSFERASE / Small molecule inhibitor bound between N-terminal and C-terminal domain of kinase / CELL CYCLE-TRANSFERASE 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 / cyclin-dependent protein serine/threonine kinase regulator 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 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 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 / 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 / cytoplasm / cytosol
Similarity search - Function
Cyclin domain, herpesvirus / Herpesviridae viral cyclin / Cyclin, herpesvirus / Cyclin-dependent kinase 6 / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin A; domain 1 / Cyclin, N-terminal ...Cyclin domain, herpesvirus / Herpesviridae viral cyclin / Cyclin, herpesvirus / Cyclin-dependent kinase 6 / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / 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-AP9 / Cyclin-dependent kinase 6 / Cyclin homolog
Similarity search - Component
Biological speciesHerpesvirus saimiri
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsSchulze-Gahmen, U. / Lu, H.
CitationJournal: J.Med.Chem. / Year: 2006
Title: Toward understanding the structural basis of cyclin-dependent kinase 6 specific inhibition.
Authors: Lu, H. / Schulze-Gahmen, U.
History
DepositionNov 16, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jun 13, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Advisory / Version format compliance
Revision 1.3Jan 24, 2018Group: Structure summary / Category: audit_author / Item: _audit_author.name
Revision 1.4Feb 14, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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: Cyclin homolog
B: Cell division protein kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,3105
Polymers63,7322
Non-polymers5783
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5570 Å2
ΔGint-37 kcal/mol
Surface area22630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.517, 71.517, 449.297
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522

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Components

#1: Protein Cyclin homolog / V-cyclin


Mass: 28665.416 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Herpesvirus saimiri (strain 11) / Genus: Rhadinovirus / Species: Saimiriine herpesvirus 2 / Strain: 11 / Gene: 72, ECLF2 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q01043
#2: Protein Cell division protein kinase 6 / Serine/threonine-protein kinase PLSTIRE


Mass: 35066.332 Da / Num. of mol.: 1 / Fragment: fragment 1-308
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK6 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q00534, EC: 2.7.1.37
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-AP9 / (2S)-2-({6-[(3-AMINO-5-CHLOROPHENYL)AMINO]-9-ISOPROPYL-9H-PURIN-2-YL}AMINO)-3-METHYLBUTAN-1-OL / AMINOPURVALANOL


Mass: 403.909 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H26ClN7O
#5: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*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: 2.6 Å3/Da / Density % sol: 52.71 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 8
Details: 50 mM Tris/HCl pH 8.0, 0.1 M CaOAc, 13% PEG 3350, 10 mM DTT, 0.1M sulfobetaine, 1mM inhibitor, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.78→50 Å / Num. all: 18422 / Num. obs: 17833 / % possible obs: 96.8 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Rsym value: 0.09 / Net I/σ(I): 15.4
Reflection shellResolution: 2.78→2.88 Å / % possible all: 0.995

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Processing

Software
NameVersionClassification
REFMAC5.2.0003refinement
HKL-2000data reduction
CCP4(TRUNCATE)data scaling
AMoREphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→20 Å / Cor.coef. Fo:Fc: 0.919 / Cor.coef. Fo:Fc free: 0.885 / SU B: 40.424 / SU ML: 0.352 / TLS residual ADP flag: LIKELY RESIDUAL / Cross valid method: THROUGHOUT / ESU R: 2.645 / ESU R Free: 0.43 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.30144 893 5.1 %RANDOM
Rwork0.23774 ---
obs0.24071 16516 96.91 %-
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: 73.703 Å2
Baniso -1Baniso -2Baniso -3
1-1.26 Å20.63 Å20 Å2
2--1.26 Å20 Å2
3----1.89 Å2
Refinement stepCycle: LAST / Resolution: 2.8→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4022 0 37 0 4059
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0224135
X-RAY DIFFRACTIONr_angle_refined_deg1.3661.9735632
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9675516
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.20524.452155
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.4115689
X-RAY DIFFRACTIONr_dihedral_angle_4_deg23.6861518
X-RAY DIFFRACTIONr_chiral_restr0.0920.2688
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.023001
X-RAY DIFFRACTIONr_nbd_refined0.2420.21952
X-RAY DIFFRACTIONr_nbtor_refined0.310.22869
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.160.2111
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.3110.231
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2010.22
X-RAY DIFFRACTIONr_mcbond_it0.421.52671
X-RAY DIFFRACTIONr_mcangle_it0.7524219
X-RAY DIFFRACTIONr_scbond_it1.12631661
X-RAY DIFFRACTIONr_scangle_it1.8154.51413
LS refinement shellResolution: 2.8→2.871 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.433 75 -
Rwork0.336 1193 -
obs--99.92 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
14.01830.0785-1.4723.44371.32045.16850.1437-0.39620.0363-0.2811-0.3423-0.3717-0.15740.22110.1985-0.0871-0.2842-0.1111-0.11970.1257-0.215739.01856.92155.436
24.5569-2.0697-0.2835.3557-0.27645.58820.2361-0.3511-1.243-0.3598-0.4861-0.91841.30790.89970.250.4387-0.2244-0.05030.14230.3440.522340.65928.89560.45
33.86672.2213-0.22514.7619-0.98144.1350.1428-0.4321-0.5909-0.2184-0.22420.45350.936-1.10890.08140.1728-0.5464-0.07210.2934-0.00490.02814.70432.99758.29
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
1X-RAY DIFFRACTION1AA8 - 2548 - 254
2X-RAY DIFFRACTION2BB9 - 1009 - 100
3X-RAY DIFFRACTION3BB101 - 305101 - 305
4X-RAY DIFFRACTION3BD401

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