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- PDB-4tth: Crystal structure of a CDK6/Vcyclin complex with inhibitor bound -

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Basic information

Entry
Database: PDB / ID: 4tth
TitleCrystal structure of a CDK6/Vcyclin complex with inhibitor bound
Components
  • Cyclin homolog
  • Cyclin-dependent kinase 6
KeywordsTRANSFERASE/CELL CYCLE/INHIBITOR / Kinase / TRANSFERASE-CELL CYCLE-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 / 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 / hematopoietic stem cell differentiation / negative regulation of osteoblast differentiation / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / cyclin-dependent protein kinase holoenzyme complex / 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-24V / Cyclin-dependent kinase 6 / Cyclin homolog
Similarity search - Component
Biological speciesSaimiriine herpesvirus 2 (Herpesvirus saimiri)
Homo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 Å
AuthorsPiper, D.E. / Walker, N. / Wang, Z.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of AMG 925, a FLT3 and CDK4 dual kinase inhibitor with preferential affinity for the activated state of FLT3.
Authors: Li, Z. / Wang, X. / Eksterowicz, J. / Gribble, M.W. / Alba, G.Q. / Ayres, M. / Carlson, T.J. / Chen, A. / Chen, X. / Cho, R. / Connors, R.V. / DeGraffenreid, M. / Deignan, J.T. / Duquette, J. ...Authors: Li, Z. / Wang, X. / Eksterowicz, J. / Gribble, M.W. / Alba, G.Q. / Ayres, M. / Carlson, T.J. / Chen, A. / Chen, X. / Cho, R. / Connors, R.V. / DeGraffenreid, M. / Deignan, J.T. / Duquette, J. / Fan, P. / Fisher, B. / Fu, J. / Huard, J.N. / Kaizerman, J. / Keegan, K.S. / Li, C. / Li, K. / Li, Y. / Liang, L. / Liu, W. / Lively, S.E. / Lo, M.C. / Ma, J. / McMinn, D.L. / Mihalic, J.T. / Modi, K. / Ngo, R. / Pattabiraman, K. / Piper, D.E. / Queva, C. / Ragains, M.L. / Suchomel, J. / Thibault, S. / Walker, N. / Wang, X. / Wang, Z. / Wanska, M. / Wehn, P.M. / Weidner, M.F. / Zhang, A.J. / Zhao, X. / Kamb, A. / Wickramasinghe, D. / Dai, K. / McGee, L.R. / Medina, J.C.
History
DepositionJun 20, 2014Deposition site: RCSB / Processing site: RCSB
SupersessionAug 6, 2014ID: 4P41
Revision 1.0Aug 6, 2014Provider: repository / Type: Initial release
Revision 1.1Oct 1, 2014Group: Database references
Revision 1.2Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Other / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_database_status / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag ..._citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_database_status.pdb_format_compatible / _pdbx_struct_oper_list.symmetry_operation / _software.classification
Revision 1.3Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / refine_hist
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin homolog
B: Cyclin-dependent kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)66,0673
Polymers65,6532
Non-polymers4151
Water18010
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4160 Å2
ΔGint-17 kcal/mol
Surface area20960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.100, 71.100, 448.995
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.) Saimiriine herpesvirus 2 (Herpesvirus saimiri)
Strain: 11 / Gene: 72, ECLF2 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q01043
#2: Protein Cyclin-dependent kinase 6 / Cell division protein kinase 6 / Serine/threonine-protein kinase PLSTIRE


Mass: 36987.328 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK6, CDKN6 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: Q00534, cyclin-dependent kinase
#3: Chemical ChemComp-24V / 9-cyclopentyl-N-(5-piperazin-1-ylpyridin-2-yl)pyrido[4,5]pyrrolo[1,2-d]pyrimidin-2-amine


Mass: 414.506 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N8
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 10 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.5 Å3/Da / Density % sol: 50.7 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop
Details: 10 mM TRIS pH 7.9, 100 mM calcium acetate, 10 mM DTT, 8-12% PEG 3350, 100 mM NDSB-201

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 12, 2007
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.9→19.68 Å / Num. obs: 16125 / % possible obs: 99.6 % / Redundancy: 11.8 % / Net I/σ(I): 28
Reflection shellResolution: 2.9→3.08 Å / Redundancy: 11.2 % / Rmerge(I) obs: 0.41 / Mean I/σ(I) obs: 6.2 / % possible all: 99.8

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Processing

Software
NameVersionClassification
PHENIX(phenix.refine: 1.8.1_1168)refinement
XDSdata scaling
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2EUF

2euf


Resolution: 2.9→19.68 Å / SU ML: 0.5 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 35.03 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3366 805 5.03 %Random selection
Rwork0.2346 ---
obs0.2396 16018 99.83 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.9→19.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3865 0 31 10 3906
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0093972
X-RAY DIFFRACTIONf_angle_d1.3165405
X-RAY DIFFRACTIONf_dihedral_angle_d17.2231441
X-RAY DIFFRACTIONf_chiral_restr0.081657
X-RAY DIFFRACTIONf_plane_restr0.005666
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.9-3.08120.40591360.27862462X-RAY DIFFRACTION100
3.0812-3.3180.40931360.27862417X-RAY DIFFRACTION100
3.318-3.650.34881310.24652481X-RAY DIFFRACTION100
3.65-4.17380.32251480.21982509X-RAY DIFFRACTION100
4.1738-5.2420.31191310.22882563X-RAY DIFFRACTION100
5.242-19.68040.32971230.22662781X-RAY DIFFRACTION100

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