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- PDB-9h8c: Human CDK8/Cyclin-C complex with inhibitor 2-9 -

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Basic information

Entry
Database: PDB / ID: 9h8c
TitleHuman CDK8/Cyclin-C complex with inhibitor 2-9
Components
  • Cyclin-C
  • Cyclin-dependent kinase 8
KeywordsTRANSCRIPTION / Kinase / Inhibitor / CDK8 / Cyclin Dependent Kinase / Cyclin / Transcription-Transferase-Inhibitor Complex
Function / homology
Function and homology information


CKM complex / G0 to G1 transition / mediator complex / RNA polymerase II CTD heptapeptide repeat Y1 kinase activity / RNA polymerase II CTD heptapeptide repeat S2 kinase activity / RNA polymerase II CTD heptapeptide repeat T4 kinase activity / RNA polymerase II CTD heptapeptide repeat S5 kinase activity / RNA polymerase II CTD heptapeptide repeat S7 kinase activity / Generic Transcription Pathway / [RNA-polymerase]-subunit kinase ...CKM complex / G0 to G1 transition / mediator complex / RNA polymerase II CTD heptapeptide repeat Y1 kinase activity / RNA polymerase II CTD heptapeptide repeat S2 kinase activity / RNA polymerase II CTD heptapeptide repeat T4 kinase activity / RNA polymerase II CTD heptapeptide repeat S5 kinase activity / RNA polymerase II CTD heptapeptide repeat S7 kinase activity / 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 / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / PPARA activates gene expression / Transcriptional regulation of white adipocyte differentiation / NOTCH1 Intracellular Domain Regulates Transcription / 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, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / Serine/threonine-protein kinase, active site ...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
: / Cyclin-C / Cyclin-dependent kinase 8
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 2.573 Å
AuthorsSomers, D.O.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2025
Title: Phenotype-Led Identification of IL-10 Upregulators in Human CD4 + T-cells and Elucidation of Their Pharmacology as Highly Selective CDK8/CDK19 Inhibitors.
Authors: Nicolle, S. / Barker, M. / Barrett, J. / Campbell, M. / Wojno-Picon, J. / Atkinson, S.J. / Aylott, H. / Kessedjian, H. / He, Y. / Messenger, C. / Roberts, E. / Spitzfaden, C. / Le, J. / ...Authors: Nicolle, S. / Barker, M. / Barrett, J. / Campbell, M. / Wojno-Picon, J. / Atkinson, S.J. / Aylott, H. / Kessedjian, H. / He, Y. / Messenger, C. / Roberts, E. / Spitzfaden, C. / Le, J. / Zinn, N. / Werner, T. / Dumpelfeld, B. / Bantscheff, M. / Somers, D.O. / Reid, H. / Thang, K. / Gobbetti, T. / Lewis, H.D.
History
DepositionOct 29, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 22, 2025Provider: repository / Type: Initial release
Revision 1.1Feb 5, 2025Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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)85,2918
Polymers84,5202
Non-polymers7716
Water4,954275
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4300 Å2
ΔGint-20 kcal/mol
Surface area28050 Å2
Unit cell
Length a, b, c (Å)71.531, 69.208, 168.237
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: 48028.863 Da / Num. of mol.: 1
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: 36491.113 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, 281 molecules

#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: isolated from a natural source / Formula: C3H8O3
#5: Chemical ChemComp-A1IS8 / 4-[(3~{S})-3-[2-[(3~{R})-3-fluoranylpyrrolidin-1-yl]pyrimidin-4-yl]piperidin-1-yl]carbonyl-1~{H}-pyrrole-2-carbonitrile


Mass: 368.408 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H21FN6O / Feature type: SUBJECT OF INVESTIGATION
#6: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 275 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.46 Å3/Da / Density % sol: 50.07 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / Details: PEG3350, MES pH6.5, HEPES pH6.8, Sodium Formate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.976 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Feb 24, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976 Å / Relative weight: 1
ReflectionResolution: 2.573→64.004 Å / Num. obs: 19966 / % possible obs: 90.7 % / Redundancy: 11.2 % / CC1/2: 0.997 / Rmerge(I) obs: 0.209 / Rpim(I) all: 0.065 / Rrim(I) all: 0.218 / Net I/σ(I): 11.2
Reflection shellResolution: 2.573→2.838 Å / Redundancy: 12.3 % / Rmerge(I) obs: 1.98 / Mean I/σ(I) obs: 1.4 / Num. unique obs: 999 / CC1/2: 0.566 / Rpim(I) all: 0.585 / Rrim(I) all: 2.066 / % possible all: 52.5

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Processing

Software
NameVersionClassification
BUSTER2.11.8 (26-JUL-2023)refinement
autoPROCdata reduction
XDS(VERSION Jan 10data reduction
autoPROC(Version 1.0.5)data scaling
Aimlessdata scaling
BUSTERphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 2.573→64 Å / Cor.coef. Fo:Fc: 0.933 / Cor.coef. Fo:Fc free: 0.889 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.39
RfactorNum. reflection% reflectionSelection details
Rfree0.2621 933 4.67 %RANDOM
Rwork0.1889 ---
obs0.1924 19966 73.2 %-
Displacement parametersBiso mean: 53.53 Å2
Baniso -1Baniso -2Baniso -3
1-2.0518 Å20 Å20 Å2
2---5.6653 Å20 Å2
3---3.6135 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: LAST / Resolution: 2.573→64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4987 0 51 275 5313
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0075200HARMONIC2
X-RAY DIFFRACTIONt_angle_deg0.887019HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1850SINUSOIDAL2
X-RAY DIFFRACTIONt_incorr_chiral_ct
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes867HARMONIC5
X-RAY DIFFRACTIONt_it5200HARMONIC10
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_omega_torsion2.75
X-RAY DIFFRACTIONt_other_torsion18.85
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_chiral_improper_torsion642SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies3HARMONIC1
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact4486SEMIHARMONIC4
LS refinement shellResolution: 2.573→2.77 Å
RfactorNum. reflection% reflection
Rfree0.3298 -6.67 %
Rwork0.2526 406 -
obs--8.15 %
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)
10.124-1.2911-1.31121.92720.75340.93550.1742-0.07240.1363-0.2754-0.17460.0016-0.1173-0.11640.00030.0427-0.0093-0.0738-0.14570.01860.05331.472668.920657.5333
21.04150.2582-0.04691.6511-0.44240.48460.00130.0903-0.0511-0.09360.04920.03810.0209-0.0184-0.05050.0245-0.016-0.0173-0.0927-0.0053-0.052710.524340.102156.4537
30.6327-0.43370.08740.41990.06461.6199-0.0075-0.05730.063-0.08740.1434-0.0092-0.01210.0681-0.1359-0.0326-0.04560.0498-0.13150.01220.0355-3.901268.297186.5482
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1{ A|0 - A|100 }
2X-RAY DIFFRACTION2{ A|101 - A|362}
3X-RAY DIFFRACTION3{ B|* }

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