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- PDB-6oqo: CDK6 in complex with Cpd24 N-(5-(6-ethyl-2,6-diazaspiro[3.3]hepta... -

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Basic information

Entry
Database: PDB / ID: 6oqo
TitleCDK6 in complex with Cpd24 N-(5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl)-5-fluoro-4-(4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-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 / 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 / Oncogene Induced Senescence / regulation of erythrocyte differentiation / 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 / 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-N1J / Cyclin-dependent kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / Resolution: 1.977 Å
AuthorsMurray, J.M. / Boenig, G.D.L.
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 / Refinement description
Category: citation / citation_author ...citation / citation_author / database_2 / refine / refine_hist
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 / _refine.pdbx_diffrn_id / _refine_hist.d_res_high / _refine_hist.d_res_low / _refine_hist.pdbx_number_atoms_nucleic_acid / _refine_hist.pdbx_number_atoms_protein

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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)33,5322
Polymers33,0691
Non-polymers4631
Water1,31573
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)103.335, 103.335, 59.851
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-N1J / N-[5-(6-ethyl-2,6-diazaspiro[3.3]heptan-2-yl)pyridin-2-yl]-5-fluoro-4-[(4R)-4-methyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a]azepin-3-yl]pyrimidin-2-amine


Mass: 462.566 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H31FN8
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 73 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.63 Å3/Da / Density % sol: 53.22 %
Crystal growTemperature: 292 K / Method: evaporation / pH: 7.5
Details: 17 % w/v PEG 3,350, 100 mM HEPES, pH 7.5, 200 mM NaCl, 20 mM L-Glutathione

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 0.999 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Dec 19, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.999 Å / Relative weight: 1
ReflectionResolution: 1.977→51.791 Å / Num. obs: 17296 / % possible obs: 97.6 % / Redundancy: 13.3 % / CC1/2: 0.999 / Rmerge(I) obs: 0.045 / Rpim(I) all: 0.013 / Rrim(I) all: 0.047 / Net I/σ(I): 25.3
Reflection shell

Diffraction-ID: 1 / % possible all: 100

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all
1.977-2.13913.32.6641730.3780.7552.77
9.871-51.79112.60.0221920.9990.0060.023

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHENIX1.14_3260refinement
PDB_EXTRACT3.25data extraction
RefinementResolution: 1.977→73.069 Å / SU ML: 0.35 / Cross valid method: THROUGHOUT / σ(F): 1.37 / Phase error: 44.63 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2641 753 4.69 %
Rwork0.2155 15300 -
obs0.2177 16053 72.35 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 176.04 Å2 / Biso mean: 73.8988 Å2 / Biso min: 32.91 Å2
Refinement stepCycle: final / Resolution: 1.977→73.069 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2132 0 34 73 2239
Biso mean--60.44 66.43 -
Num. residues----269
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.977-2.12970.4273160.353943244810
2.1297-2.3440.41211120.32352120223251
2.344-2.68320.31922190.298641984417100
2.6832-3.38060.33962020.264742234425100
3.3806-73.11880.22592040.182943274531100
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)
10.77590.61820.16430.9321-0.50290.94330.3996-0.21070.84040.5565-0.2949-0.3766-0.52430.7615-0.00060.96730.18260.14750.6668-0.06140.746434.340938.8664-6.9955
23.24060.9128-2.02454.6061-1.71564.197-0.0298-0.025-0.2789-0.5412-0.0933-0.22980.34480.36250.00020.61880.1344-0.00820.3464-0.02960.375420.97429.2729-2.8075
33.7964-1.0001-0.98574.7822-0.30035.58250.204-0.16910.1188-0.28910.09280.5598-0.0789-0.92030.00850.33150.0774-0.08710.57050.04540.53562.495735.47484.8065
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 11 through 55 )A11 - 55
2X-RAY DIFFRACTION2chain 'A' and (resid 56 through 161 )A56 - 161
3X-RAY DIFFRACTION3chain 'A' and (resid 162 through 301 )A162 - 301

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