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- PDB-5i5z: CDK8-CYCC IN COMPLEX WITH 8-(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2l... -

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Basic information

Entry
Database: PDB / ID: 5i5z
TitleCDK8-CYCC IN COMPLEX WITH 8-(1-Methyl-2,2-dioxo-2,3-dihydro-1H-2l6-benzo[c]isothiazol-5-yl)-[1,6]naphthyridine-2-carboxylic acid methylamide
Components
  • Cyclin-C
  • Cyclin-dependent kinase 8
KeywordsTRANSFERASE / CDK8 KINASE / CYCLIN C
Function / homology
Function and homology information


CKM complex / G0 to G1 transition / negative regulation of triglyceride metabolic process / mediator complex / Generic Transcription Pathway / [RNA-polymerase]-subunit kinase / cyclin-dependent protein serine/threonine kinase regulator activity / negative regulation of Notch signaling pathway / RSV-host interactions / cyclin-dependent kinase ...CKM complex / G0 to G1 transition / negative regulation of triglyceride metabolic process / mediator complex / Generic Transcription Pathway / [RNA-polymerase]-subunit kinase / cyclin-dependent protein serine/threonine kinase regulator activity / negative regulation of Notch signaling pathway / RSV-host interactions / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / cyclin-dependent protein kinase holoenzyme complex / ubiquitin ligase complex / RNA polymerase II CTD heptapeptide repeat kinase activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / PPARA activates gene expression / NOTCH1 Intracellular Domain Regulates Transcription / Transcriptional regulation of white adipocyte differentiation / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / ubiquitin protein ligase activity / protein kinase activity / protein ubiquitination / protein serine kinase activity / protein serine/threonine kinase activity / nucleolus / positive regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / ATP binding / identical protein binding / nucleus
Similarity search - Function
Cyclin, C-terminal domain 2 / Cyclin C-terminal domain / 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 ...Cyclin, C-terminal domain 2 / Cyclin C-terminal domain / 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-68U / FORMIC ACID / Cyclin-C / Cyclin-dependent kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.6 Å
AuthorsMusil, D. / Blagg, J. / Mallinger, A.
CitationJournal: Acs Med.Chem.Lett. / Year: 2016
Title: 2,8-Disubstituted-1,6-Naphthyridines and 4,6-Disubstituted-Isoquinolines with Potent, Selective Affinity for CDK8/19.
Authors: Mallinger, A. / Schiemann, K. / Rink, C. / Sejberg, J. / Honey, M.A. / Czodrowski, P. / Stubbs, M. / Poeschke, O. / Busch, M. / Schneider, R. / Schwarz, D. / Musil, D. / Burke, R. / Urbahns, ...Authors: Mallinger, A. / Schiemann, K. / Rink, C. / Sejberg, J. / Honey, M.A. / Czodrowski, P. / Stubbs, M. / Poeschke, O. / Busch, M. / Schneider, R. / Schwarz, D. / Musil, D. / Burke, R. / Urbahns, K. / Workman, P. / Wienke, D. / Clarke, P.A. / Raynaud, F.I. / Eccles, S.A. / Esdar, C. / Rohdich, F. / Blagg, J.
History
DepositionFeb 15, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Apr 13, 2016Provider: repository / Type: Initial release
Revision 1.1Jul 6, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase 8
B: Cyclin-C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)75,2355
Polymers74,7742
Non-polymers4603
Water88349
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4230 Å2
ΔGint-26 kcal/mol
Surface area29330 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.749, 71.282, 171.953
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Cyclin-dependent kinase 8 / Cell division protein kinase 8 / Mediator complex subunit CDK8 / Mediator of RNA polymerase II ...Cell division protein kinase 8 / Mediator complex subunit CDK8 / Mediator of RNA polymerase II transcription subunit CDK8 / Protein kinase K35


Mass: 43233.039 Da / Num. of mol.: 1 / Fragment: KINASE DOMAIN, RESIDUES 3-405
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK8 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P49336, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-C / SRB11 homolog / hSRB11


Mass: 31541.121 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNC / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P24863
#3: Chemical ChemComp-68U / N-methyl-8-(1-methyl-2,2-dioxo-2,3-dihydro-1H-2lambda~6~,1-benzothiazol-5-yl)-1,6-naphthyridine-2-carboxamide


Mass: 368.410 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H16N4O3S
#4: Chemical ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: CH2O2
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 49 / 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: 3.1 Å3/Da / Density % sol: 59.4 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.9 / Details: 20% PEG3350, 0.2 M sodium formate, pH 6.9

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.6→85.98 Å / Num. obs: 27530 / % possible obs: 97.2 % / Observed criterion σ(I): 0 / Redundancy: 4.1 % / Rmerge(I) obs: 0.08 / Net I/σ(I): 17.7
Reflection shellResolution: 2.6→2.85 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.503 / % possible all: 97.2

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.2.0005refinement
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4f6s

4f6s


Resolution: 2.6→85.98 Å / Cor.coef. Fo:Fc: 0.905 / Cor.coef. Fo:Fc free: 0.867 / SU B: 25.361 / SU ML: 0.257 / Cross valid method: THROUGHOUT / ESU R: 0.586 / ESU R Free: 0.321 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.27423 926 3.5 %RANDOM
Rwork0.23741 ---
obs0.23873 25840 97.23 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 42.716 Å2
Baniso -1Baniso -2Baniso -3
1--1.13 Å20 Å20 Å2
2---0.57 Å20 Å2
3---1.7 Å2
Refinement stepCycle: LAST / Resolution: 2.6→85.98 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5064 0 32 49 5145
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0225095
X-RAY DIFFRACTIONr_bond_other_d0.0020.024612
X-RAY DIFFRACTIONr_angle_refined_deg1.2241.9646912
X-RAY DIFFRACTIONr_angle_other_deg0.933310660
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.065606
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.63823.391233
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.76815853
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.2861530
X-RAY DIFFRACTIONr_chiral_restr0.0720.2749
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.025597
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021081
X-RAY DIFFRACTIONr_nbd_refined0.180.2989
X-RAY DIFFRACTIONr_nbd_other0.1340.24195
X-RAY DIFFRACTIONr_nbtor_refined0.1660.22433
X-RAY DIFFRACTIONr_nbtor_other0.0740.22593
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1030.289
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0840.21
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1540.247
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.080.24
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.65523987
X-RAY DIFFRACTIONr_mcbond_other0.29921218
X-RAY DIFFRACTIONr_mcangle_it2.08934926
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.07142457
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.33261986
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: 2.6→2.668 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.445 63 -
Rwork0.365 1885 -
obs--97.21 %

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