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- PDB-6oql: CDK6 in complex with Cpd13 (R)-5-fluoro-4-(4-methyl-5,6,7,8-tetra... -

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Basic information

Entry
Database: PDB / ID: 6oql
TitleCDK6 in complex with Cpd13 (R)-5-fluoro-4-(4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl)-N-(5-(4-methylpiperazin-1-yl)pyridin-2-yl)pyrimidin-2-amine
ComponentsCyclin-dependent kinase 6
KeywordsTRANSFERASE/TRANSFERASE inhibitor / kinase / TRANSFERASE / 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 / 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 / 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-dependent kinase 6 / 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
Similarity search - Domain/homology
Chem-N1A / Cyclin-dependent kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.707 Å
AuthorsMurray, J.M.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2019
Title: Design of a brain-penetrant CDK4/6 inhibitor for glioblastoma.
Authors: Bronner, S.M. / Merrick, K.A. / Murray, J. / Salphati, L. / Moffat, J.G. / Pang, J. / Sneeringer, C.J. / Dompe, N. / Cyr, P. / Purkey, H. / Boenig, G.L. / Li, J. / Kolesnikov, A. / Larouche- ...Authors: Bronner, S.M. / Merrick, K.A. / Murray, J. / Salphati, L. / Moffat, J.G. / Pang, J. / Sneeringer, C.J. / Dompe, N. / Cyr, P. / Purkey, H. / Boenig, G.L. / Li, J. / Kolesnikov, A. / Larouche-Gauthier, R. / Lai, K.W. / Shen, X. / Aubert-Nicol, S. / Chen, Y.C. / Cheong, J. / Crawford, J.J. / Hafner, M. / Haghshenas, P. / Jakalian, A. / Leclerc, J.P. / Lim, N.K. / O'Brien, T. / Plise, E.G. / Shalan, H. / Sturino, C. / Wai, J. / Xiao, Y. / Yin, J. / Zhao, L. / Gould, S. / Olivero, A. / Heffron, T.P.
History
DepositionApr 26, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 29, 2020Provider: repository / Type: Initial release
Revision 1.1Aug 11, 2021Group: Database references / Category: citation / citation_author / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Oct 11, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase 6
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,5062
Polymers33,0691
Non-polymers4371
Water724
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)101.668, 101.668, 60.113
Angle α, β, γ (deg.)90.000, 90.000, 90.000
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: 33069.055 Da / Num. of mol.: 1 / Fragment: kinase domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK6, CDKN6 / Plasmid: pAcGP67 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: Q00534, cyclin-dependent kinase
#2: Chemical ChemComp-N1A / 5-fluoro-N-[5-(4-methylpiperazin-1-yl)pyridin-2-yl]-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine


Mass: 436.528 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H29FN8 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 2.35 Å3/Da / Density % sol: 47.63 %
Crystal growTemperature: 292 K / Method: evaporation / pH: 6 / Details: 13-17% PEG 3350, 80 mM NH4NO3, 100 mM MES pH 6.0

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Apr 11, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 2.693→71.89 Å / Num. obs: 8609 / % possible obs: 99.9 % / Redundancy: 6.5 % / CC1/2: 1 / Rmerge(I) obs: 0.065 / Rpim(I) all: 0.028 / Rrim(I) all: 0.071 / Net I/σ(I): 14.7 / Num. measured all: 56195
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
2.693-2.7025.42.213456850.5251.0432.4540.7100
12.479-71.895.80.0235579610.010.02636.699

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5L2I

5l2i


Resolution: 2.707→36.263 Å / SU ML: 0.51 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 40.58
RfactorNum. reflection% reflection
Rfree0.2529 372 4.98 %
Rwork0.2036 --
obs0.2062 7474 88.07 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 214.21 Å2 / Biso mean: 123.3085 Å2 / Biso min: 78.64 Å2
Refinement stepCycle: final / Resolution: 2.707→36.263 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2080 0 32 4 2116
Biso mean--111.2 120.19 -
Num. residues----263
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 3

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.7071-3.09860.3354940.29381705179964
3.0986-3.90320.31691430.261826762819100
3.9032-36.2660.22951350.181627212856100
Refinement TLS params.Method: refined / Origin x: 13.581 Å / Origin y: 32.9429 Å / Origin z: -0.1206 Å
111213212223313233
T1.2851 Å20.2194 Å2-0.1706 Å2-0.791 Å2-0.0261 Å2--0.9578 Å2
L4.7084 °2-0.7923 °2-2.2898 °2-2.5966 °2-0.3227 °2--5.4472 °2
S0.3529 Å °-0.0968 Å °-0.1065 Å °-0.7074 Å °-0.2012 Å °0.1153 Å °0.3248 Å °-0.1113 Å °0.0013 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1allA11 - 301
2X-RAY DIFFRACTION1allB4000
3X-RAY DIFFRACTION1allW5 - 15

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