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- PDB-5acb: Crystal Structure of the Human Cdk12-Cyclink Complex -

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Basic information

Entry
Database: PDB / ID: 5acb
TitleCrystal Structure of the Human Cdk12-Cyclink Complex
Components
  • CYCLIN-DEPENDENT KINASE 12
  • CYCLIN-K
KeywordsTRANSFERASE
Function / homology
Function and homology information


cyclin K-CDK12 complex / cyclin K-CDK13 complex / nuclear cyclin-dependent protein kinase holoenzyme complex / regulation of MAP kinase activity / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / negative regulation of stem cell differentiation / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation of DNA-templated transcription, elongation / [RNA-polymerase]-subunit kinase ...cyclin K-CDK12 complex / cyclin K-CDK13 complex / nuclear cyclin-dependent protein kinase holoenzyme complex / regulation of MAP kinase activity / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / negative regulation of stem cell differentiation / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation of DNA-templated transcription, elongation / [RNA-polymerase]-subunit kinase / cyclin-dependent protein serine/threonine kinase regulator activity / regulation of cyclin-dependent protein serine/threonine kinase activity / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RNA polymerase II transcribes snRNA genes / regulation of signal transduction / cyclin-dependent kinase / Formation of HIV elongation complex in the absence of HIV Tat / cyclin-dependent protein serine/threonine kinase activity / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / RNA Polymerase II Pre-transcription Events / cyclin binding / RNA polymerase II CTD heptapeptide repeat kinase activity / RNA splicing / TP53 Regulates Transcription of DNA Repair Genes / positive regulation of transcription elongation by RNA polymerase II / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / mRNA processing / transcription by RNA polymerase II / protein autophosphorylation / protein kinase activity / nuclear speck / cell cycle / cell division / protein serine kinase activity / DNA damage response / host cell nucleus / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus
Similarity search - Function
Cyclin-T2-like, C-terminal domain / Haspin like kinase domain / Cyclin, C-terminal domain / Cyclin, C-terminal domain / Cyclin_C / Cyclin/Cyclin-like subunit Ssn8 / Cyclin-like / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain ...Cyclin-T2-like, C-terminal domain / Haspin like kinase domain / Cyclin, C-terminal domain / Cyclin, C-terminal domain / Cyclin_C / Cyclin/Cyclin-like subunit Ssn8 / 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-5I1 / Cyclin-K / Cyclin-K / Cyclin-dependent kinase 12
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsDixon Clarke, S.E. / Elkins, J.M. / Pike, A.C.W. / Mackenzie, A. / Goubin, S. / Strain-Damerell, C. / Mahajan, P. / Tallant, C. / Chalk, R. / Wiggers, H. ...Dixon Clarke, S.E. / Elkins, J.M. / Pike, A.C.W. / Mackenzie, A. / Goubin, S. / Strain-Damerell, C. / Mahajan, P. / Tallant, C. / Chalk, R. / Wiggers, H. / Kopec, J. / Fitzpatrick, F. / Burgess-Brown, N. / Carpenter, E.P. / von Delft, F. / Arrowsmith, C.H. / Edwards, A.M. / Bountra, C. / Bullock, A.
CitationJournal: Nat.Chem.Biol. / Year: 2016
Title: Covalent Targeting of Remote Cysteine Residues to Develop Cdk12 and Cdk13 Inhibitors.
Authors: Zhang, T. / Kwiatkowski, N. / Olson, C.M. / Dixon-Clarke, S.E. / Abraham, B.J. / Greifenberg, A.K. / Ficarro, S.B. / Elkins, J.M. / Liang, Y. / Hannett, N.M. / Manz, T. / Hao, M. / ...Authors: Zhang, T. / Kwiatkowski, N. / Olson, C.M. / Dixon-Clarke, S.E. / Abraham, B.J. / Greifenberg, A.K. / Ficarro, S.B. / Elkins, J.M. / Liang, Y. / Hannett, N.M. / Manz, T. / Hao, M. / Bartkowiak, B. / Greenleaf, A.L. / Marto, J.A. / Geyer, M. / Bullock, A.N. / Young, R.A. / Gray, N.S.
History
DepositionAug 14, 2015Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 15, 2016Provider: repository / Type: Initial release
Revision 1.1Aug 31, 2016Group: Database references
Revision 1.2Sep 21, 2016Group: Database references
Revision 1.3Oct 5, 2016Group: Database references

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: CYCLIN-K
B: CYCLIN-K
C: CYCLIN-DEPENDENT KINASE 12
D: CYCLIN-DEPENDENT KINASE 12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)141,4466
Polymers140,3264
Non-polymers1,1202
Water0
1
B: CYCLIN-K
C: CYCLIN-DEPENDENT KINASE 12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,7233
Polymers70,1632
Non-polymers5601
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3640 Å2
ΔGint-12.6 kcal/mol
Surface area26210 Å2
MethodPISA
2
A: CYCLIN-K
D: CYCLIN-DEPENDENT KINASE 12
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,7233
Polymers70,1632
Non-polymers5601
Water0
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3320 Å2
ΔGint-12.6 kcal/mol
Surface area25000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.780, 148.690, 91.580
Angle α, β, γ (deg.)90.00, 93.81, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein CYCLIN-K / CCNK


Mass: 30443.148 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFB-LIC-BSE / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: G3V5E1, UniProt: O75909*PLUS
#2: Protein CYCLIN-DEPENDENT KINASE 12 / / CDC2-RELATED KINASE / ARGININE/SERINE-RICH / CRKRS / CELL DIVISION CYCLE 2-RELATED PROTEIN KINASE 7 ...CDC2-RELATED KINASE / ARGININE/SERINE-RICH / CRKRS / CELL DIVISION CYCLE 2-RELATED PROTEIN KINASE 7 / CDC2-RELATED PROTEIN KINASE 7 / CELL DIVISION PROTEIN KINASE 12 / HCDK12


Mass: 39719.922 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PFB-LIC-BSE / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: Q9NYV4, cyclin-dependent kinase
#3: Chemical ChemComp-5I1 / N-[4-[(3R)-3-[[5-chloranyl-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]piperidin-1-yl]carbonylphenyl]-4-(dimethylamino)butanamide


Mass: 560.090 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H34ClN7O2

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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: 2.41 Å3/Da / Density % sol: 48.96 % / Description: NONE
Crystal growDetails: 10% PEG8000, 0.2M MAGNESIUM CHLORIDE, 0.1M HEPES PH7.0

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9765
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9765 Å / Relative weight: 1
ReflectionResolution: 2.7→41.3 Å / Num. obs: 36020 / % possible obs: 98.7 % / Observed criterion σ(I): 0 / Redundancy: 3 % / Rmerge(I) obs: 0.07 / Net I/σ(I): 12.5

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Processing

Software
NameVersionClassification
REFMAC5.8.0123refinement
xia2data reduction
Aimlessdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.7→91.38 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.902 / SU B: 17.327 / SU ML: 0.338 / Cross valid method: THROUGHOUT / ESU R Free: 0.372 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.26187 1756 4.9 %RANDOM
Rwork0.2214 ---
obs0.22339 34240 98.64 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 60.778 Å2
Baniso -1Baniso -2Baniso -3
1-0.27 Å20 Å2-1.55 Å2
2--4.76 Å20 Å2
3----4.78 Å2
Refinement stepCycle: LAST / Resolution: 2.7→91.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8993 0 80 0 9073
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0199311
X-RAY DIFFRACTIONr_bond_other_d0.0030.028651
X-RAY DIFFRACTIONr_angle_refined_deg1.1371.96912646
X-RAY DIFFRACTIONr_angle_other_deg0.9743.00319868
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.55951123
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.45524.177419
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.842151535
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.4051543
X-RAY DIFFRACTIONr_chiral_restr0.0630.21384
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02110421
X-RAY DIFFRACTIONr_gen_planes_other0.0020.022156
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.1446.2254513
X-RAY DIFFRACTIONr_mcbond_other2.1436.2234512
X-RAY DIFFRACTIONr_mcangle_it3.6349.3235629
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it1.9566.334798
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.7→2.77 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.386 122 -
Rwork0.341 2581 -
obs--98.97 %

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