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- PDB-5fgk: CDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro... -

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Basic information

Entry
Database: PDB / ID: 5fgk
TitleCDK8-CYCC IN COMPLEX WITH 8-[3-(3-Amino-1H-indazol-6-yl)-5-chloro- pyridine-4-yl]-2,8-diaza-spiro[4.5]decan-1-one
Components
  • Cyclin-C
  • Cyclin-dependent kinase 8
KeywordsTRANSFERASE / CDK8 KINASE / CYCLIN C
Function / homology
Function and homology information


CKM complex / negative regulation of triglyceride metabolic process / G0 to G1 transition / mediator complex / Generic Transcription Pathway / [RNA-polymerase]-subunit kinase / cyclin-dependent protein serine/threonine kinase regulator activity / negative regulation of Notch signaling pathway / cyclin-dependent protein kinase holoenzyme complex / cyclin-dependent kinase ...CKM complex / negative regulation of triglyceride metabolic process / G0 to G1 transition / mediator complex / Generic Transcription Pathway / [RNA-polymerase]-subunit kinase / cyclin-dependent protein serine/threonine kinase regulator activity / negative regulation of Notch signaling pathway / cyclin-dependent protein kinase holoenzyme complex / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / 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 / Constitutive Signaling by NOTCH1 PEST Domain Mutants / Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants / Transcriptional regulation of white adipocyte differentiation / ubiquitin protein ligase activity / protein ubiquitination / protein kinase activity / phosphorylation / 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-5XG / FORMIC ACID / Cyclin-C / Cyclin-dependent kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 Å
AuthorsMusil, D. / Blagg, J. / Mallinger, A.
CitationJournal: J.Med.Chem. / Year: 2016
Title: Discovery of Potent, Selective, and Orally Bioavailable Small-Molecule Modulators of the Mediator Complex-Associated Kinases CDK8 and CDK19.
Authors: Mallinger, A. / Schiemann, K. / Rink, C. / Stieber, F. / Calderini, M. / Crumpler, S. / Stubbs, M. / Adeniji-Popoola, O. / Poeschke, O. / Busch, M. / Czodrowski, P. / Musil, D. / Schwarz, D. ...Authors: Mallinger, A. / Schiemann, K. / Rink, C. / Stieber, F. / Calderini, M. / Crumpler, S. / Stubbs, M. / Adeniji-Popoola, O. / Poeschke, O. / Busch, M. / Czodrowski, P. / Musil, D. / Schwarz, D. / Ortiz-Ruiz, M.J. / Schneider, R. / Thai, C. / Valenti, M. / de Haven Brandon, A. / Burke, R. / Workman, P. / Dale, T. / Wienke, D. / Clarke, P.A. / Esdar, C. / Raynaud, F.I. / Eccles, S.A. / Rohdich, F. / Blagg, J.
History
DepositionDec 20, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Feb 3, 2016Provider: repository / Type: Initial release
Revision 1.1Feb 24, 2016Group: Database references

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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)75,01513
Polymers74,0932
Non-polymers92111
Water3,423190
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5120 Å2
ΔGint-17 kcal/mol
Surface area28960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.943, 71.928, 177.926
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 2 types, 2 molecules AB

#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: 42552.211 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

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Non-polymers , 5 types, 201 molecules

#3: Chemical ChemComp-5XG / 8-[3-(3-azanyl-2~{H}-indazol-6-yl)-5-chloranyl-pyridin-4-yl]-2,8-diazaspiro[4.5]decan-1-one


Mass: 396.873 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H21ClN6O
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#6: Chemical
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: CH2O2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 190 / 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: 3.26 Å3/Da / Density % sol: 62.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 0 / Details: RESERVOIR SOLUTION : pH 6.90

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Data collection

DiffractionMean temperature: 110 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1.00008 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: 1.00008 Å / Relative weight: 1
ReflectionResolution: 2.36→88.96 Å / Num. obs: 38677 / % possible obs: 97.4 % / Observed criterion σ(I): 0 / Redundancy: 2.8 % / Biso Wilson estimate: 48.365 Å2 / Rmerge F obs: 0.994 / Rmerge(I) obs: 0.082 / Rrim(I) all: 0.1 / Χ2: 0.961 / Net I/σ(I): 9.17 / Num. measured all: 105854
Reflection shellResolution: 2.36→2.61 Å / Redundancy: 2.8 % / Rmerge F obs: 0.995 / Rmerge(I) obs: 0.483 / Mean I/σ(I) obs: 2.31 / Num. measured obs: 387 / Num. possible: 182 / Num. unique obs: 146 / Rrim(I) all: 0.043 / Rejects: 0 / % possible all: 99.1

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.5.0109refinement
PDB_EXTRACT3.15data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.36→88.96 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.927 / SU B: 14.89 / SU ML: 0.159 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.279 / ESU R Free: 0.212 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2369 1208 3.2 %RANDOM
obs-36455 97.38 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso max: 102.73 Å2 / Biso mean: 34.592 Å2 / Biso min: 22.72 Å2
Baniso -1Baniso -2Baniso -3
1-2 Å20 Å20 Å2
2---1.9 Å20 Å2
3----0.1 Å2
Refinement stepCycle: final / Resolution: 2.36→88.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4952 0 61 190 5203
Biso mean--71.63 44.81 -
Num. residues----597
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0224985
X-RAY DIFFRACTIONr_bond_other_d0.0020.023428
X-RAY DIFFRACTIONr_angle_refined_deg1.2521.9646749
X-RAY DIFFRACTIONr_angle_other_deg1.03838248
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.6615598
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.31223.484221
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.82515814
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.521526
X-RAY DIFFRACTIONr_chiral_restr0.0750.2732
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0215480
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021048
X-RAY DIFFRACTIONr_mcbond_it1.58723017
X-RAY DIFFRACTIONr_mcbond_other0.40321196
X-RAY DIFFRACTIONr_mcangle_it2.67834831
X-RAY DIFFRACTIONr_scbond_it4.10241968
X-RAY DIFFRACTIONr_scangle_it5.75361918
LS refinement shellResolution: 2.363→2.424 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.328 99 -
Rwork0.276 2687 -
all-2786 -
obs--98.69 %

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