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- PDB-9d8u: Crystal structure of CDK6 in complex with atirmociclib -

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Basic information

Entry
Database: PDB / ID: 9d8u
TitleCrystal structure of CDK6 in complex with atirmociclib
ComponentsCyclin-dependent kinase 6
KeywordsTRANSFERASE / Kinase / Inhibitor / Cancer
Function / homology
Function and homology information


cyclin D2-CDK6 complex / cyclin D3-CDK6 complex / cyclin D1-CDK6 complex / cell dedifferentiation / 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 / Drug-mediated inhibition of CDK4/CDK6 activity / FBXO family protein binding / lateral ventricle development / negative regulation of myeloid cell differentiation ...cyclin D2-CDK6 complex / cyclin D3-CDK6 complex / cyclin D1-CDK6 complex / cell dedifferentiation / 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 / Drug-mediated inhibition of CDK4/CDK6 activity / 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 / regulation of cell motility / gliogenesis / 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 cell cycle / negative regulation of cellular senescence / negative regulation of cell differentiation / negative regulation of osteoblast differentiation / hematopoietic stem cell differentiation / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / cyclin-dependent protein kinase holoenzyme complex / ruffle / regulation of G2/M transition of mitotic cell cycle / Notch signaling pathway / cyclin binding / regulation of erythrocyte differentiation / Oncogene Induced Senescence / response to virus / G1/S transition of mitotic cell cycle / positive regulation of fibroblast proliferation / negative regulation of epithelial cell proliferation / Cyclin D associated events in G1 / T cell differentiation in thymus / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / Oxidative Stress Induced Senescence / regulation of cell cycle / protein phosphorylation / negative regulation of cell population proliferation / cell division / 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
: / Cyclin-dependent kinase 6
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsJohnson, E. / Chen, P. / Ferre, R.A. / Deihl, W. / Yu, X. / He, Y.-A.
Funding support United States, 1items
OrganizationGrant numberCountry
Not funded United States
CitationJournal: Cancer Cell / Year: 2025
Title: CDK4 selective inhibition improves preclinical anti-tumor efficacy and safety.
Authors: Palmer, C.L. / Boras, B. / Pascual, B. / Li, N. / Li, D. / Garza, S. / Huser, N. / Yuan, J.T. / Cianfrogna, J.A. / Sung, T. / McMillan, E. / Wei, N. / Carmody, J. / Kang, A.N. / Darensburg, ...Authors: Palmer, C.L. / Boras, B. / Pascual, B. / Li, N. / Li, D. / Garza, S. / Huser, N. / Yuan, J.T. / Cianfrogna, J.A. / Sung, T. / McMillan, E. / Wei, N. / Carmody, J. / Kang, A.N. / Darensburg, S. / Dodd, T. / Oakley, J.V. / Solowiej, J. / Nguyen, L. / Orr, S.T.M. / Chen, P. / Johnson, E. / Yu, X. / Diehl, W.C. / Gallego, G.M. / Jalaie, M. / Ferre, R.A. / Cho-Schultz, S. / Shen, H. / Deal, J.G. / Zhang, Q. / Baffi, T.R. / Xu, M. / Roh, W. / Lapira-Miller, J. / Goudeau, J. / Yu, Y. / Gupta, R. / Kim, K. / Dann, S.G. / Kan, Z. / Kath, J.C. / Nair, S.K. / Miller, N. / Murray, B.W. / Nager, A.R. / Quinlan, C. / Petroski, M.D. / Zhang, C. / Sacaan, A. / VanArsdale, T. / Anders, L.
History
DepositionAug 20, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 26, 2025Provider: repository / Type: Initial release

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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)35,4832
Polymers35,0191
Non-polymers4641
Water1,60389
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)102.100, 102.100, 59.900
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
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-A1AZ4 / Atirmociclib


Mass: 463.933 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H27ClFN5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 89 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.23 Å3/Da / Density % sol: 44.81 %
Crystal growTemperature: 286.15 K / Method: vapor diffusion, sitting drop / pH: 6
Details: Well Ingredients: Salt: 0.133 M Ammonium Nitrate Precipitant: 5.09 %w/v PEG 3350 Buffer: 0.1 M MES (pH 6.00) Plate setup temperature: 21 C Plate incubation temperature: 13 C Drop volume from ...Details: Well Ingredients: Salt: 0.133 M Ammonium Nitrate Precipitant: 5.09 %w/v PEG 3350 Buffer: 0.1 M MES (pH 6.00) Plate setup temperature: 21 C Plate incubation temperature: 13 C Drop volume from well: 0.3 uL Drop protein volume: 0.3 uL

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Data collection

DiffractionMean temperature: 98.15 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 4, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.852→72.196 Å / Num. obs: 14833 / % possible obs: 94.5 % / Redundancy: 6.7 % / CC1/2: 0.999 / Rpim(I) all: 0.021 / Net I/σ(I): 17.7
Reflection shellResolution: 1.852→2.103 Å / Redundancy: 5.3 % / Mean I/σ(I) obs: 1.8 / Num. unique obs: 741 / CC1/2: 0.615 / Rpim(I) all: 0.47 / % possible all: 73.4

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (21-NOV-2022)refinement
Aimlessdata scaling
XDSdata reduction
autoBUSTERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2→29.95 Å / Cor.coef. Fo:Fc: 0.943 / Cor.coef. Fo:Fc free: 0.929 / SU R Cruickshank DPI: 0.304 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.298 / SU Rfree Blow DPI: 0.218 / SU Rfree Cruickshank DPI: 0.222
RfactorNum. reflection% reflectionSelection details
Rfree0.2533 946 6.51 %RANDOM
Rwork0.217 ---
obs0.2194 14532 69.4 %-
Displacement parametersBiso mean: 52.71 Å2
Baniso -1Baniso -2Baniso -3
1-0.9283 Å20 Å20 Å2
2--0.9283 Å20 Å2
3----1.8566 Å2
Refine analyzeLuzzati coordinate error obs: 0.3 Å
Refinement stepCycle: LAST / Resolution: 2→29.95 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2084 0 32 90 2206
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0082164HARMONIC2
X-RAY DIFFRACTIONt_angle_deg12935HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d748SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes382HARMONIC5
X-RAY DIFFRACTIONt_it2164HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion3.07
X-RAY DIFFRACTIONt_other_torsion20.11
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion274SEMIHARMONIC5
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_contact1705SEMIHARMONIC4
LS refinement shellResolution: 2→2.08 Å / Total num. of bins used: 48
RfactorNum. reflection% reflection
Rfree0.2335 -11.94 %
Rwork0.2997 273 -
all0.2921 310 -
obs--14.23 %
Refinement TLS params.Method: refined / Origin x: 18.0023 Å / Origin y: 36.9825 Å / Origin z: 0.5186 Å
111213212223313233
T-0.0339 Å20.1108 Å2-0.0329 Å2-0.0101 Å2-0.0219 Å2---0.0815 Å2
L0.2282 °2-0.228 °2-0.0522 °2-1.1705 °2-0.0629 °2--1.0802 °2
S-0.0048 Å °-0.1448 Å °-0.0213 Å °-0.098 Å °0.0313 Å °0.0894 Å °-0.0777 Å °-0.0066 Å °-0.0264 Å °
Refinement TLS groupSelection details: { A|* }

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