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- PDB-5idn: CDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-y... -

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Basic information

Entry
Database: PDB / ID: 5idn
TitleCDK8-CYCC IN COMPLEX WITH [(S)-2-(4-Chloro-phenyl)-pyrrolidin-1-yl]-(3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)-methanone
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-6A7 / FORMIC ACID / Cyclin-C / Cyclin-dependent kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.26 Å
AuthorsMusil, D. / Blagg, J. / Mallinger, A. / Czodrowski, P. / Schiemann, K.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Structure-Based Optimization of Potent, Selective, and Orally Bioavailable CDK8 Inhibitors Discovered by High-Throughput Screening.
Authors: Czodrowski, P. / Mallinger, A. / Wienke, D. / Esdar, C. / Poschke, O. / Busch, M. / Rohdich, F. / Eccles, S.A. / Ortiz-Ruiz, M.J. / Schneider, R. / Raynaud, F.I. / Clarke, P.A. / Musil, D. / ...Authors: Czodrowski, P. / Mallinger, A. / Wienke, D. / Esdar, C. / Poschke, O. / Busch, M. / Rohdich, F. / Eccles, S.A. / Ortiz-Ruiz, M.J. / Schneider, R. / Raynaud, F.I. / Clarke, P.A. / Musil, D. / Schwarz, D. / Dale, T. / Urbahns, K. / Blagg, J. / Schiemann, K.
History
DepositionFeb 24, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0Dec 21, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 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)75,58210
Polymers74,9032
Non-polymers6798
Water3,369187
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4600 Å2
ΔGint-22 kcal/mol
Surface area29060 Å2
MethodPISA
Unit cell
Length a, b, c (Å)70.460, 73.467, 168.020
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 43247.066 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: 31656.207 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 , 4 types, 195 molecules

#3: Chemical ChemComp-6A7 / [(2S)-2-(4-chlorophenyl)pyrrolidin-1-yl](3-methyl-1H-pyrazolo[3,4-b]pyridin-5-yl)methanone


Mass: 340.807 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17ClN4O
#4: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#5: Chemical
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: CH2O2
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 187 / 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: 59.6 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.9 / Details: 20% PEG 3350, 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: May 15, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.26→84.01 Å / Num. obs: 40902 / % possible obs: 98.2 % / Observed criterion σ(I): 0 / Redundancy: 3.7 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 14.9
Reflection shellResolution: 2.26→2.51 Å / Redundancy: 3.7 % / Rmerge(I) obs: 0.504 / % possible all: 97.8

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Processing

Software
NameVersionClassification
XDSdata reduction
XSCALEdata scaling
REFMAC5.2.0005refinement
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS
Starting model: 4F6S

4f6s


Resolution: 2.26→84.01 Å / Cor.coef. Fo:Fc: 0.941 / Cor.coef. Fo:Fc free: 0.925 / SU B: 6.383 / SU ML: 0.159 / Cross valid method: THROUGHOUT / ESU R: 0.259 / ESU R Free: 0.208 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25299 1353 3.3 %RANDOM
Rwork0.21989 ---
obs0.22102 39547 98.16 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 38.236 Å2
Baniso -1Baniso -2Baniso -3
1-0.86 Å20 Å20 Å2
2--0.98 Å20 Å2
3----1.85 Å2
Refinement stepCycle: LAST / Resolution: 2.26→84.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5000 0 46 187 5233
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0225013
X-RAY DIFFRACTIONr_bond_other_d0.0020.024531
X-RAY DIFFRACTIONr_angle_refined_deg1.131.9596805
X-RAY DIFFRACTIONr_angle_other_deg0.926310450
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.75606
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.43423.649222
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.02815816
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.4831524
X-RAY DIFFRACTIONr_chiral_restr0.0640.2743
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025538
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021052
X-RAY DIFFRACTIONr_nbd_refined0.160.2923
X-RAY DIFFRACTIONr_nbd_other0.1280.24245
X-RAY DIFFRACTIONr_nbtor_refined0.1590.22397
X-RAY DIFFRACTIONr_nbtor_other0.0750.22418
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0830.2206
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0760.25
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1690.245
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1030.25
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.623976
X-RAY DIFFRACTIONr_mcbond_other0.2621215
X-RAY DIFFRACTIONr_mcangle_it1.95734905
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.68742355
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it3.82661900
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: 2.26→2.319 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.357 118 -
Rwork0.362 2859 -
obs--98.38 %

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