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- PDB-9qcx: Cryo-EM structure of apo-CAK-CDK2-cyclin A2 -

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Basic information

Entry
Database: PDB / ID: 9qcx
TitleCryo-EM structure of apo-CAK-CDK2-cyclin A2
Components
  • CDK-activating kinase assembly factor MAT1
  • Cyclin-A2
  • Cyclin-H
  • Cyclin-dependent kinase 2
  • Cyclin-dependent kinase 7
KeywordsTRANSFERASE / Complex / cell cycle / kinase
Function / homology
Function and homology information


: / RNA polymerase II CTD heptapeptide repeat S5 kinase activity / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / ventricular system development / cellular response to luteinizing hormone stimulus / snRNA transcription by RNA polymerase II / CAK-ERCC2 complex / transcription factor TFIIK complex / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 ...: / RNA polymerase II CTD heptapeptide repeat S5 kinase activity / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / ventricular system development / cellular response to luteinizing hormone stimulus / snRNA transcription by RNA polymerase II / CAK-ERCC2 complex / transcription factor TFIIK complex / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / adult heart development / transcription factor TFIIH core complex / transcription factor TFIIH holo complex / male pronucleus / cyclin-dependent protein serine/threonine kinase activator activity / female pronucleus / cellular response to cocaine / [RNA-polymerase]-subunit kinase / response to glucagon / RNA Polymerase I Transcription Termination / positive regulation of DNA biosynthetic process / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / RNA Pol II CTD phosphorylation and interaction with CE during HIV infection / RNA Pol II CTD phosphorylation and interaction with CE / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / HIV Transcription Initiation / RNA Polymerase II HIV Promoter Escape / Transcription of the HIV genome / RNA Polymerase II Promoter Escape / RNA Polymerase II Transcription Pre-Initiation And Promoter Opening / RNA Polymerase II Transcription Initiation / RNA Polymerase II Transcription Initiation And Promoter Clearance / Formation of the Early Elongation Complex / Formation of the HIV-1 Early Elongation Complex / X chromosome / mRNA Capping / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / regulation of DNA replication / telomere maintenance in response to DNA damage / microtubule organizing center / centrosome duplication / RNA Polymerase I Transcription Initiation / regulation of G1/S transition of mitotic cell cycle / G0 and Early G1 / cochlea development / RNA polymerase II transcribes snRNA genes / Telomere Extension By Telomerase / animal organ regeneration / Activation of the pre-replicative complex / ATP-dependent activity, acting on DNA / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / Activation of ATR in response to replication stress / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / Cyclin E associated events during G1/S transition / Formation of HIV elongation complex in the absence of HIV Tat / Cyclin A:Cdk2-associated events at S phase entry / Cyclin A/B1/B2 associated events during G2/M transition / cyclin-dependent protein kinase holoenzyme complex / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / cellular response to platelet-derived growth factor stimulus / mitotic G1 DNA damage checkpoint signaling / RNA Polymerase II Pre-transcription Events / positive regulation of smooth muscle cell proliferation / RNA polymerase II CTD heptapeptide repeat kinase activity / cellular response to nitric oxide / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / nucleotide-excision repair / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / RNA Polymerase I Promoter Escape
Similarity search - Function
CyclinH/Ccl1 / Cyclin-dependent kinase 7 / Cdk-activating kinase assembly factor MAT1/Tfb3 / Cdk-activating kinase assembly factor MAT1, centre / CDK-activating kinase assembly factor MAT1 / Zinc finger, C3HC4 type (RING finger) / Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / Cyclin, C-terminal domain 2 / Cyclin C-terminal domain ...CyclinH/Ccl1 / Cyclin-dependent kinase 7 / Cdk-activating kinase assembly factor MAT1/Tfb3 / Cdk-activating kinase assembly factor MAT1, centre / CDK-activating kinase assembly factor MAT1 / Zinc finger, C3HC4 type (RING finger) / Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / Cyclin, C-terminal domain 2 / Cyclin C-terminal domain / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, C-terminal domain / Cyclin_C / Ubiquitin interacting motif / Ubiquitin-interacting motif (UIM) domain profile. / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type / 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-A2 / Cyclin-dependent kinase 2 / Cyclin-dependent kinase 7 / Cyclin-H / CDK-activating kinase assembly factor MAT1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsCushing, V.I. / Greber, B.J. / McGeoch, A.J.S. / Feng, J.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/V009354/1 United Kingdom
The Institute of Cancer Research (ICR) United Kingdom
CitationJournal: Science / Year: 2025
Title: Structural basis of T-loop-independent recognition and activation of CDKs by the CDK-activating kinase.
Authors: Victoria I Cushing / Amy J S McGeoch / Sophie L Williams / Theodoros I Roumeliotis / Junjie Feng / Lucy M Dan / Jyoti S Choudhary / Norman E Davey / Basil J Greber /
Abstract: Cyclin-dependent kinases (CDKs) are prototypical regulators of the cell cycle. The CDK-activating kinase (CAK) acts as a master regulator of CDK activity by catalyzing the activating phosphorylation ...Cyclin-dependent kinases (CDKs) are prototypical regulators of the cell cycle. The CDK-activating kinase (CAK) acts as a master regulator of CDK activity by catalyzing the activating phosphorylation of CDKs on a conserved threonine residue within the regulatory T-loop. However, structural data illuminating the mechanism by which the CAK recognizes and activates CDKs have remained elusive. Here, we determine high-resolution structures of the CAK in complex with CDK2 and CDK2-cyclin A2 by cryogenic electron microscopy. Our structures reveal a T-loop-independent kinase-kinase interface with contributions from both kinase lobes. Computational analysis and structures of CAK in complex with CDK1-cyclin B1 and CDK11 indicate that these structures represent the general architecture of CAK-CDK complexes. These results advance our mechanistic understanding of cell cycle regulation and kinase signaling cascades.
History
DepositionMar 5, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 15, 2025Provider: repository / Type: Initial release
Revision 1.0Oct 15, 2025Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: CDK-activating kinase assembly factor MAT1
I: Cyclin-H
J: Cyclin-dependent kinase 7
K: Cyclin-dependent kinase 2
L: Cyclin-A2


Theoretical massNumber of molelcules
Total (without water)202,6215
Polymers202,6215
Non-polymers00
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 CDK-activating kinase assembly factor MAT1 / CDK7/cyclin-H assembly factor / Cyclin-G1-interacting protein / Menage a trois / RING finger ...CDK7/cyclin-H assembly factor / Cyclin-G1-interacting protein / Menage a trois / RING finger protein 66 / RING finger protein MAT1 / p35 / p36


Mass: 38132.340 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MNAT1, CAP35, MAT1, RNF66 / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P51948
#2: Protein Cyclin-H / MO15-associated protein / p34 / p37


Mass: 37721.508 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNH / Production host: Trichoplusia ni (cabbage looper) / References: UniProt: P51946
#3: Protein Cyclin-dependent kinase 7 / 39 kDa protein kinase / p39 Mo15 / CDK-activating kinase 1 / Cell division protein kinase 7 / ...39 kDa protein kinase / p39 Mo15 / CDK-activating kinase 1 / Cell division protein kinase 7 / Serine/threonine-protein kinase 1 / TFIIH basal transcription factor complex kinase subunit


Mass: 43651.070 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK7, CAK, CAK1, CDKN7, MO15, STK1 / Production host: Trichoplusia ni (cabbage looper)
References: UniProt: P50613, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#4: Protein Cyclin-dependent kinase 2 / Cell division protein kinase 2 / p33 protein kinase


Mass: 34248.750 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK2, CDKN2 / Production host: Escherichia coli (E. coli) / References: UniProt: P24941, cyclin-dependent kinase
#5: Protein Cyclin-A2 / Cyclin-A / Cyclin A


Mass: 48867.805 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNA2, CCN1, CCNA / Production host: Escherichia coli (E. coli) / References: UniProt: P20248
Has ligand of interestN
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

Component
IDNameTypeDetailsEntity IDParent-IDSource
1CAK-CDK2-cyclin A2 complexCOMPLEXCDK-activating kinase (CAK) in complex with CDK2-cyclin A2all0MULTIPLE SOURCES
2CDK-activating kinase (CAK)COMPLEX#1-#31RECOMBINANT
3CDK2-cyclin A2COMPLEX#4-#51RECOMBINANT
Molecular weight
IDEntity assembly-IDValue (°)Experimental value
110.20 MDaNO
210.12 MDaNO
310.083 MDaNO
Source (natural)
IDEntity assembly-IDOrganismNcbi tax-ID
22Homo sapiens (human)9606
33Homo sapiens (human)9606
Source (recombinant)
IDEntity assembly-IDOrganismNcbi tax-ID
22Trichoplusia ni (cabbage looper)7111
33Escherichia coli (E. coli)562
Buffer solutionpH: 7.5
Buffer component
IDConc.NameFormulaBuffer-ID
125 mMHEPES1
2150 mMSodium chlorideNaCl1
310 mMMagnesium chlorideMgCl21
40.5 mMAMP-PNP1
SpecimenConc.: 0.4 mg/ml / Embedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid material: GOLD / Grid mesh size: 300 divisions/in. / Grid type: UltrAuFoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 278 K

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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 magnification: 215000 X / Nominal defocus max: 2000 nm / Nominal defocus min: 600 nm / Cs: 2.7 mm
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 70 e/Å2 / Film or detector model: TFS FALCON 4i (4k x 4k) / Num. of grids imaged: 1 / Num. of real images: 10934
EM imaging opticsEnergyfilter name: TFS Selectris X

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Processing

EM software
IDNameVersionCategory
1cryoSPARCparticle selection
2EPUimage acquisition
4cryoSPARCCTF correction
5RELION5CTF correction
8UCSF ChimeraXmodel fitting
10RELION5initial Euler assignment
11RELION5final Euler assignment
12RELION5classification
13RELION53D reconstruction
14PHENIX1.21-5207model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 106829 / Algorithm: FOURIER SPACE / Symmetry type: POINT
Atomic model buildingProtocol: RIGID BODY FIT / Space: REAL
Atomic model building
IDPDB-ID 3D fitting-IDAccession codeInitial refinement model-IDSource nameType
18P6Y

8p6y

18P6Y1PDBexperimental model
21OKV

1okv

11OKV2PDBexperimental model

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