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- PDB-8tqc: Structure of the human CDK8 kinase module -

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Basic information

Entry
Database: PDB / ID: 8tqc
TitleStructure of the human CDK8 kinase module
Components
  • Cyclin-C
  • Cyclin-dependent kinase 8
  • Mediator of RNA polymerase II transcription subunit 12
  • Mediator of RNA polymerase II transcription subunit 13
KeywordsTRANSCRIPTION / Mediator / CDK8 / MED12 / MED13 / CKM.
Function / homology
Function and homology information


axis elongation involved in somitogenesis / embryonic neurocranium morphogenesis / CKM complex / G0 to G1 transition / post-anal tail morphogenesis / embryonic brain development / endoderm development / mediator complex / Generic Transcription Pathway / oligodendrocyte development ...axis elongation involved in somitogenesis / embryonic neurocranium morphogenesis / CKM complex / G0 to G1 transition / post-anal tail morphogenesis / embryonic brain development / endoderm development / mediator complex / Generic Transcription Pathway / oligodendrocyte development / nuclear vitamin D receptor binding / nuclear thyroid hormone receptor binding / [RNA-polymerase]-subunit kinase / Wnt signaling pathway, planar cell polarity pathway / triglyceride homeostasis / cyclin-dependent protein serine/threonine kinase regulator activity / spinal cord development / RSV-host interactions / negative regulation of Notch signaling pathway / somatic stem cell population maintenance / ubiquitin ligase complex / positive regulation of transcription initiation by RNA polymerase II / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / Schwann cell development / cyclin-dependent protein kinase holoenzyme complex / RNA polymerase II CTD heptapeptide repeat kinase activity / cholesterol homeostasis / transcription coregulator activity / neural tube closure / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / PPARA activates gene expression / beta-catenin binding / 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 / ubiquitin protein ligase activity / heart development / MLL4 and MLL3 complexes regulate expression of PPARG target genes in adipogenesis and hepatic steatosis / transcription coactivator activity / protein kinase activity / protein ubiquitination / RNA polymerase II cis-regulatory region sequence-specific DNA binding / protein serine kinase activity / protein serine/threonine kinase activity / chromatin binding / positive regulation of DNA-templated transcription / nucleolus / positive regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / ATP binding / identical protein binding / nucleus / membrane
Similarity search - Function
Mediator complex, subunit Med12, catenin-binding / Mediator complex, subunit Med12, LCEWAV-domain / : / Eukaryotic Mediator 12 catenin-binding domain / Eukaryotic Mediator 12 subunit domain / Mediator complex, subunit Med12 / MID domain of medPIWI / Transcription mediator complex subunit Med12 / MID domain of medPIWI / Transcription mediator complex subunit Med12 ...Mediator complex, subunit Med12, catenin-binding / Mediator complex, subunit Med12, LCEWAV-domain / : / Eukaryotic Mediator 12 catenin-binding domain / Eukaryotic Mediator 12 subunit domain / Mediator complex, subunit Med12 / MID domain of medPIWI / Transcription mediator complex subunit Med12 / MID domain of medPIWI / Transcription mediator complex subunit Med12 / Mediator complex subunit Med13, C-terminal / : / Mediator complex subunit 13 C-terminal domain / 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 / Mediator of RNA polymerase II transcription subunit 12 / Mediator of RNA polymerase II transcription subunit 13
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.8 Å
AuthorsChen, S.F. / Chao, T.C. / Kim, H.J. / Tang, H.C. / Khadka, S. / Li, T. / Murakami, K. / Boyer, T.G. / Tsai, K.L.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS) United States
CitationJournal: Mol Cell / Year: 2024
Title: Structural basis of the human transcriptional Mediator regulated by its dissociable kinase module.
Authors: Ti-Chun Chao / Shin-Fu Chen / Hee Jong Kim / Hui-Chi Tang / Hsiang-Ching Tseng / An Xu / Leon Palao / Subash Khadka / Tao Li / Mo-Fan Huang / Dung-Fang Lee / Kenji Murakami / Thomas G Boyer / Kuang-Lei Tsai /
Abstract: The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex ...The eukaryotic transcriptional Mediator comprises a large core (cMED) and a dissociable CDK8 kinase module (CKM). cMED recruits RNA polymerase II (RNA Pol II) and promotes pre-initiation complex formation in a manner repressed by the CKM through mechanisms presently unknown. Herein, we report cryoelectron microscopy structures of the complete human Mediator and its CKM. The CKM binds to multiple regions on cMED through both MED12 and MED13, including a large intrinsically disordered region (IDR) in the latter. MED12 and MED13 together anchor the CKM to the cMED hook, positioning CDK8 downstream and proximal to the transcription start site. Notably, the MED13 IDR obstructs the recruitment of RNA Pol II/MED26 onto cMED by direct occlusion of their respective binding sites, leading to functional repression of cMED-dependent transcription. Combined with biochemical and functional analyses, these structures provide a conserved mechanistic framework to explain the basis for CKM-mediated repression of cMED function.
History
DepositionAug 6, 2023Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 9, 2024Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
C: Mediator of RNA polymerase II transcription subunit 12
D: Mediator of RNA polymerase II transcription subunit 13
A: Cyclin-dependent kinase 8
B: Cyclin-C
hetero molecules


Theoretical massNumber of molelcules
Total (without water)569,6706
Polymers569,5394
Non-polymers1312
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein Mediator of RNA polymerase II transcription subunit 12


Mass: 243354.891 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MED12 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q93074
#2: Protein Mediator of RNA polymerase II transcription subunit 13 / Activator-recruited cofactor 250 kDa component / ARC250 / Mediator complex subunit 13 / Thyroid ...Activator-recruited cofactor 250 kDa component / ARC250 / Mediator complex subunit 13 / Thyroid hormone receptor-associated protein 1 / Thyroid hormone receptor-associated protein complex 240 kDa component / Trap240 / Vitamin D3 receptor-interacting protein complex component DRIP250 / DRIP250


Mass: 239535.906 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MED13, ARC250, KIAA0593, THRAP1, TRAP240 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: Q9UHV7
#3: Protein Cyclin-dependent kinase 8


Mass: 53368.668 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK8 / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P49336
#4: Protein Cyclin-C


Mass: 33279.691 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNC / Production host: Baculovirus expression vector pFastBac1-HM / References: UniProt: P24863
#5: Chemical ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Zn / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: human CDK8 kinase module / Type: COMPLEX / Entity ID: #1-#4 / Source: RECOMBINANT
Source (natural)Organism: Homo sapiens (human)
Source (recombinant)Organism: Baculovirus expression vector pFastBac1-HM
Buffer solutionpH: 7.9
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationInstrument: FEI VITROBOT MARK III / Cryogen name: ETHANE / Humidity: 100 %

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 3000 nm / Nominal defocus min: 600 nm
Image recordingElectron dose: 64 e/Å2 / Film or detector model: GATAN K2 QUANTUM (4k x 4k)

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Processing

EM softwareName: PHENIX / Category: model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.8 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 122015 / Symmetry type: POINT

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