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- PDB-7sj3: Structure of CDK4-Cyclin D3 bound to abemaciclib -

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Basic information

Entry
Database: PDB / ID: 7sj3
TitleStructure of CDK4-Cyclin D3 bound to abemaciclib
Components
  • Cyclin-dependent kinase 4
  • G1/S-specific cyclin-D3
KeywordsCELL CYCLE / CDK / cyclin / kinase / inhibitor complex
Function / homology
Function and homology information


cyclin D3-CDK4 complex / cyclin D1-CDK4 complex / cyclin D2-CDK4 complex / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 / cellular response to ionomycin / regulation of transcription initiation by RNA polymerase II / 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 ...cyclin D3-CDK4 complex / cyclin D1-CDK4 complex / cyclin D2-CDK4 complex / Evasion of Oncogene Induced Senescence Due to Defective p16INK4A binding to CDK4 / Evasion of Oxidative Stress Induced Senescence Due to Defective p16INK4A binding to CDK4 / cellular response to ionomycin / regulation of transcription initiation by RNA polymerase II / 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 / regulation of type B pancreatic cell proliferation / Transcriptional regulation by RUNX2 / cellular response to phorbol 13-acetate 12-myristate / mitotic cell cycle phase transition / cyclin-dependent protein serine/threonine kinase activator activity / Regulation of RUNX1 Expression and Activity / cyclin-dependent protein serine/threonine kinase regulator activity / PTK6 Regulates Cell Cycle / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / positive regulation of cyclin-dependent protein serine/threonine kinase activity / cyclin-dependent protein kinase holoenzyme complex / bicellular tight junction / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / T cell proliferation / positive regulation of G2/M transition of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / cellular response to interleukin-4 / cyclin binding / response to organic substance / Ubiquitin-dependent degradation of Cyclin D / G1/S transition of mitotic cell cycle / MAPK6/MAPK4 signaling / Oncogene Induced Senescence / SCF(Skp2)-mediated degradation of p27/p21 / RMTs methylate histone arginines / Meiotic recombination / Transcriptional regulation of white adipocyte differentiation / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / positive regulation of fibroblast proliferation / regulation of cell population proliferation / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / Oxidative Stress Induced Senescence / nuclear membrane / cellular response to lipopolysaccharide / transcription regulator complex / regulation of cell cycle / response to xenobiotic stimulus / positive regulation of protein phosphorylation / cell division / protein phosphorylation / protein serine kinase activity / positive regulation of cell population proliferation / chromatin / nucleolus / protein kinase binding / negative regulation of transcription by RNA polymerase II / signal transduction / nucleoplasm / ATP binding / nucleus / cytosol / cytoplasm
Similarity search - Function
Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma ...Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / 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-6ZV / Cyclin-dependent kinase 4 / G1/S-specific cyclin-D3
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.51 Å
AuthorsHilgers, M.T. / Pelletier, L.A.
Funding support United States, 1items
OrganizationGrant numberCountry
Other privateNA United States
CitationJournal: To Be Published
Title: Structure of CDK4-Cyclin D3 bound to abemaciclib
Authors: Hilgers, M.T. / Pelletier, L.A.
History
DepositionOct 15, 2021Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Oct 18, 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 4
B: G1/S-specific cyclin-D3
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,5643
Polymers64,0572
Non-polymers5071
Water81145
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4070 Å2
ΔGint-19 kcal/mol
Surface area23160 Å2
MethodPISA
Unit cell
Length a, b, c (Å)117.654, 117.654, 170.278
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522
Space group name HallP652(x,y,z+1/12)
Symmetry operation#1: x,y,z
#2: x-y,x,z+5/6
#3: y,-x+y,z+1/6
#4: -y,x-y,z+2/3
#5: -x+y,-x,z+1/3
#6: x-y,-y,-z
#7: -x,-x+y,-z+1/3
#8: -x,-y,z+1/2
#9: y,x,-z+2/3
#10: -y,-x,-z+1/6
#11: -x+y,y,-z+1/2
#12: x,x-y,-z+5/6
Components on special symmetry positions
IDModelComponents
11B-310-

HOH

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Components

#1: Protein Cyclin-dependent kinase 4 / / Cell division protein kinase 4 / PSK-J3


Mass: 34762.672 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P11802, cyclin-dependent kinase
#2: Protein G1/S-specific cyclin-D3


Mass: 29294.258 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCND3 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P30281
#3: Chemical ChemComp-6ZV / N-{5-[(4-ethylpiperazin-1-yl)methyl]pyridin-2-yl}-5-fluoro-4-[4-fluoro-2-methyl-1-(propan-2-yl)-1H-benzimidazol-6-yl]py rimidin-2-amine / Abemaciclib / Abemaciclib


Mass: 506.593 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H32F2N8 / Feature type: SUBJECT OF INVESTIGATION / Comment: medication, inhibitor*YM
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 2.95 Å3/Da / Density % sol: 57.98 % / Description: single, rod-shaped
Crystal growTemperature: 294 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 100mM MES pH 6.5, 10% PEG 8000, 200mM sodium acetate, 10mM TCEP

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Data collection

DiffractionMean temperature: 103 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 31-ID / Wavelength: 0.97931 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Oct 14, 2016
RadiationMonochromator: Kohzu HLD-4 with diamond 111 crystals / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97931 Å / Relative weight: 1
ReflectionResolution: 2.51→19.78 Å / Num. obs: 24294 / % possible obs: 99.7 % / Redundancy: 21.6 % / CC1/2: 0.999 / Rmerge(I) obs: 0.105 / Rpim(I) all: 0.023 / Rrim(I) all: 0.107 / Net I/σ(I): 21.5 / Num. measured all: 523823
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
2.51-2.6522.11.5987654234630.8240.3431.6342.699.8
7.94-19.7818.10.041148708220.9990.010.04357.992.9

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Processing

Software
NameVersionClassification
PHENIX1.19.2refinement
autoPROC1.0.4data reduction
Aimless0.7.4data scaling
PHASER2.5.5phasing
Coot0.9.3model building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 2F2C, 3G33

2f2c

3g33


Resolution: 2.51→19.78 Å / SU ML: 0.3152 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 23.8421
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2335 1241 5.11 %
Rwork0.1996 23044 -
obs0.2013 24285 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 89.25 Å2
Refinement stepCycle: LAST / Resolution: 2.51→19.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4015 0 40 45 4100
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00424145
X-RAY DIFFRACTIONf_angle_d0.82265629
X-RAY DIFFRACTIONf_chiral_restr0.0516639
X-RAY DIFFRACTIONf_plane_restr0.0053715
X-RAY DIFFRACTIONf_dihedral_angle_d14.4611546
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.51-2.610.32251510.2692486X-RAY DIFFRACTION99.66
2.61-2.730.36391170.25552522X-RAY DIFFRACTION99.62
2.73-2.870.25621500.2342484X-RAY DIFFRACTION99.62
2.87-3.050.28351400.22652520X-RAY DIFFRACTION99.7
3.05-3.290.28651340.23322536X-RAY DIFFRACTION99.81
3.29-3.620.24891310.21392544X-RAY DIFFRACTION99.81
3.62-4.140.23421340.18582579X-RAY DIFFRACTION99.82
4.14-5.190.19921540.17132603X-RAY DIFFRACTION99.93
5.2-19.780.20421300.18942770X-RAY DIFFRACTION99.45
Refinement TLS params.

L11: 0 °2 / L12: 0 °2 / L13: 0 °2 / L22: 0 °2 / L23: 0 °2 / L33: 0 °2 / S11: 0 Å ° / S12: 0 Å ° / S13: 0 Å ° / S21: 0 Å ° / S22: 0 Å ° / S23: 0 Å ° / S31: 0 Å ° / S32: 0 Å ° / S33: 0 Å ° / T11: 0 Å2 / T12: 0 Å2 / T13: 0 Å2 / T22: 0 Å2 / T23: 0 Å2 / T33: 0 Å2 / Method: refined / Refine-ID: X-RAY DIFFRACTION

IDOrigin x (Å)Origin y (Å)Origin z (Å)
115.9934939192-44.919626241918.9412670739
225.2965863919-38.790804221213.0668572424
313.7968026652-37.41496588512.4549824202
420.3169252264-29.04401313071.82556197347
511.6057962402-33.0021011593-10.4397535236
612.5181470542-29.567326668-23.0961133311
715.5077051812-18.4105183639-8.84851492156
845.7162550865-36.5858752212.02272309302
942.6037415167-48.33767572294.76507713558
1052.3316022537-26.7418699416-6.72730367685
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION

IDRefine TLS-IDSelection detailsAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11chain 'A' and (resid 2 through 25 )AB2 - 252 - 25
22chain 'A' and (resid 26 through 80 )AB26 - 8026 - 73
33chain 'A' and (resid 81 through 114 )AB81 - 11474 - 100
44chain 'A' and (resid 115 through 171 )AB115 - 171101 - 157
55chain 'A' and (resid 173 through 230 )AB173 - 230159 - 216
66chain 'A' and (resid 231 through 265 )AB231 - 265217 - 245
77chain 'A' and (resid 266 through 295 )AB266 - 295246 - 275
88chain 'B' and (resid 11 through 70 )BC11 - 701 - 60
99chain 'B' and (resid 71 through 156 )BC71 - 15661 - 146
1010chain 'B' and (resid 157 through 255 )BC157 - 255147 - 242

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