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- PDB-6tpa: CDK8/CyclinC in complex with drug ETP-50775 -

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Basic information

Entry
Database: PDB / ID: 6tpa
TitleCDK8/CyclinC in complex with drug ETP-50775
Components
  • Cyclin-C
  • Cyclin-dependent kinase 8
KeywordsCELL CYCLE / Cell division Kinase Inhibitor
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 / RSV-host interactions / negative regulation of Notch signaling pathway / cyclin-dependent protein kinase holoenzyme complex ...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 / RSV-host interactions / 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 kinase activity / protein ubiquitination / 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, 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. ...Cyclin, C-terminal domain 2 / Cyclin C-terminal domain / Cyclin/Cyclin-like subunit Ssn8 / 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
FORMIC ACID / (2~{R})-butane-1,2-diol / Chem-NZ8 / Cyclin-C / Cyclin-dependent kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsMunoz, I.G. / Pastor, J. / Martinez, S.
CitationJournal: Eur.J.Med.Chem. / Year: 2020
Title: Pyrido[2,3-b][1,5]benzoxazepin-5(6H)-one derivatives as CDK8 inhibitors.
Authors: Martinez-Gonzalez, S. / Garcia, A.B. / Albarran, M.I. / Cebria, A. / Amezquita-Alves, A. / Garcia-Campos, F.J. / Martinez-Gago, J. / Martinez-Torrecuadrada, J. / Munoz, I. / Blanco-Aparicio, C. / Pastor, J.
History
DepositionDec 12, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 18, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 24, 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)81,88119
Polymers80,4432
Non-polymers1,43917
Water1,58588
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5010 Å2
ΔGint-28 kcal/mol
Surface area26970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.985, 72.339, 189.127
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: 46962.789 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK8
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: P49336, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-C / SRB11 homolog / hSRB11


Mass: 33479.953 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNC
Production host: Insect cell expression vector pTIE1 (others)
References: UniProt: P24863

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Non-polymers , 4 types, 105 molecules

#3: Chemical ChemComp-NZ8 / 1-[4-chloranyl-3-(trifluoromethyl)phenyl]-3-(5-oxidanylidene-6-pyridin-4-yl-pyrido[2,3-b][1,5]benzoxazepin-9-yl)urea


Mass: 525.867 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H15ClF3N5O3 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 12 / Source method: obtained synthetically / Formula: CH2O2
#5: Chemical
ChemComp-NZ5 / (2~{R})-butane-1,2-diol


Mass: 90.121 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C4H10O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 88 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3.06 Å3/Da / Density % sol: 59.81 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / Details: 20% PEG 3350, 200mM NaFormate, 3% Butanediol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9282 Å
DetectorType: DECTRIS PILATUS3 S 6M / Detector: PIXEL / Date: Mar 15, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9282 Å / Relative weight: 1
ReflectionResolution: 2.7998→94.564 Å / Num. obs: 24925 / % possible obs: 99.5 % / Redundancy: 5.5 % / CC1/2: 0.99 / Net I/σ(I): 14.5
Reflection shellResolution: 2.7998→2.91 Å / Num. unique obs: 1817 / CC1/2: 0.89

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Processing

Software
NameVersionClassification
PHENIX1.15.2_3472refinement
XDSdata reduction
PDB_EXTRACT3.25data extraction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5CEI

5cei


Resolution: 2.8→94.564 Å / SU ML: 0.43 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 27.76
RfactorNum. reflection% reflection
Rfree0.2636 1241 4.98 %
Rwork0.2257 --
obs0.2277 24925 99.31 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 99.85 Å2 / Biso mean: 50.7182 Å2 / Biso min: 23.32 Å2
Refinement stepCycle: final / Resolution: 2.8→94.564 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4729 0 97 88 4914
Biso mean--52.89 47.61 -
Num. residues----601
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection Rwork% reflection obs (%)
2.8-2.91190.38771560.3251256099
2.9119-3.04440.31861280.28142594100
3.0444-3.2050.29741240.2442259999
3.205-3.40580.25121210.23712639100
3.4058-3.66870.30621220.21872626100
3.6687-4.03790.23071310.19792636100
4.0379-4.62220.25831420.1905262799
4.6222-5.82340.23451700.2122646100
5.8234-100.25241470.2409275798

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