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- PDB-6qtg: Crystal structure of human CDK8/CYCC in complex with BI-1347 -

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Basic information

Entry
Database: PDB / ID: 6qtg
TitleCrystal structure of human CDK8/CYCC in complex with BI-1347
Components
  • Cyclin-C
  • Cyclin-dependent kinase 8
KeywordsCELL CYCLE / Inhibitor / Complex
Function / homology
Function and homology information


CKM complex / G0 to G1 transition / 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 kinase / cyclin-dependent protein serine/threonine kinase activity ...CKM complex / G0 to G1 transition / 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 kinase / cyclin-dependent protein serine/threonine kinase activity / cyclin-dependent protein kinase holoenzyme 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 / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / protein kinase activity / 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 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-JH8 / Cyclin-C / Cyclin-dependent kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.7 Å
AuthorsBoettcher, J.
CitationJournal: Mol.Cancer Ther. / Year: 2020
Title: Selective and Potent CDK8/19 Inhibitors Enhance NK-Cell Activity and Promote Tumor Surveillance.
Authors: Hofmann, M.H. / Mani, R. / Engelhardt, H. / Impagnatiello, M.A. / Carotta, S. / Kerenyi, M. / Lorenzo-Herrero, S. / Bottcher, J. / Scharn, D. / Arnhof, H. / Zoephel, A. / Schnitzer, R. / ...Authors: Hofmann, M.H. / Mani, R. / Engelhardt, H. / Impagnatiello, M.A. / Carotta, S. / Kerenyi, M. / Lorenzo-Herrero, S. / Bottcher, J. / Scharn, D. / Arnhof, H. / Zoephel, A. / Schnitzer, R. / Gerstberger, T. / Sanderson, M.P. / Rajgolikar, G. / Goswami, S. / Vasu, S. / Ettmayer, P. / Gonzalez, S. / Pearson, M. / McConnell, D.B. / Kraut, N. / Muthusamy, N. / Moll, J.
History
DepositionFeb 25, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 18, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 22, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Jan 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 / refine
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _refine.pdbx_diffrn_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)80,6713
Polymers80,3142
Non-polymers3561
Water3,621201
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3090 Å2
ΔGint-23 kcal/mol
Surface area27900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)69.539, 73.922, 168.310
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: 46890.664 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK8 / Production host: Trichoplusia (butterflies/moths)
References: UniProt: P49336, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-C / SRB11 homolog / hSRB11


Mass: 33423.824 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNC / Production host: Trichoplusia lectula (butterflies/moths) / References: UniProt: P24863
#3: Chemical ChemComp-JH8 / 2-[4-(4-isoquinolin-4-ylphenyl)pyrazol-1-yl]-~{N},~{N}-dimethyl-ethanamide


Mass: 356.420 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H20N4O
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 201 / 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: 2.69 Å3/Da / Density % sol: 54.33 %
Crystal growTemperature: 278 K / Method: vapor diffusion, sitting drop
Details: 32-38% Morpheus Precipitant Mix 4 10 mmol/L Morpheus Buffer System 1 100 mM Morpheus Amino Acids Mix 2% DMSO
PH range: 6-7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Aug 4, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.702→84.2 Å / Num. obs: 24333 / % possible obs: 99.3 % / Redundancy: 10 % / Biso Wilson estimate: 69.6 Å2 / Net I/σ(I): 12.5
Reflection shellResolution: 2.702→2.749 Å

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Processing

Software
NameVersionClassification
BUSTER2.11.7refinement
XDSdata reduction
STARANISOdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3RGF

3rgf


Resolution: 2.7→37.6 Å / Cor.coef. Fo:Fc: 0.922 / Cor.coef. Fo:Fc free: 0.899 / SU R Cruickshank DPI: 0.64 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.73 / SU Rfree Blow DPI: 0.288 / SU Rfree Cruickshank DPI: 0.287
RfactorNum. reflection% reflectionSelection details
Rfree0.231 1111 4.58 %RANDOM
Rwork0.201 ---
obs0.202 24270 99 %-
Displacement parametersBiso mean: 56.98 Å2
Baniso -1Baniso -2Baniso -3
1-12.0763 Å20 Å20 Å2
2---22.3502 Å20 Å2
3---10.2739 Å2
Refine analyzeLuzzati coordinate error obs: 0.36 Å
Refinement stepCycle: LAST / Resolution: 2.7→37.6 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4916 0 27 201 5144
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0085075HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.946854HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1790SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes829HARMONIC5
X-RAY DIFFRACTIONt_it5075HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.35
X-RAY DIFFRACTIONt_other_torsion17.15
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion629SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5915SEMIHARMONIC4
LS refinement shellResolution: 2.7→2.72 Å / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.248 -5.76 %
Rwork0.2568 458 -
all0.2563 486 -
obs--98.02 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.9020.2856-0.13160.8526-0.07110.9512-0.09860.1476-0.0202-0.08760.1042-0.0227-0.04360.026-0.0056-0.12230.02240.0091-0.00590.0168-0.11472.8417-10.355815.0399
21.76530.59260.25951.6221-0.11593.03420.08060.03010.08390.07780.03530.0246-0.08160.0077-0.1158-0.20940.0780.0309-0.09410.0859-0.0526-16.2969-22.942644.5129
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|* }
2X-RAY DIFFRACTION2{ B|* }

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