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- EMDB-52205: Cryo-EM structure of CAK (CDK7 D97N mutant) in complex with THZ1 -

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Basic information

Entry
Database: EMDB / ID: EMD-52205
TitleCryo-EM structure of CAK (CDK7 D97N mutant) in complex with THZ1
Map dataSharpened, post-processed EM map
Sample
  • Complex: CDK-activating kinase (CAK)
    • Protein or peptide: CDK-activating kinase assembly factor MAT1
    • Protein or peptide: Cyclin-H
    • Protein or peptide: Cyclin-dependent kinase 7
  • Ligand: N-(3-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)-4-{[4-(dimethylamino)butanoyl]amino}benzamide
  • Ligand: water
KeywordsKinase / complex / heterotrimer / TRANSFERASE
Function / homology
Function and homology information


RNA polymerase II CTD heptapeptide repeat S5 kinase activity / ventricular system development / snRNA transcription by RNA polymerase II / CAK-ERCC2 complex / transcription factor TFIIK complex / adult heart development / transcription factor TFIIH core complex / transcription factor TFIIH holo complex / cyclin-dependent protein serine/threonine kinase activator activity / [RNA-polymerase]-subunit kinase ...RNA polymerase II CTD heptapeptide repeat S5 kinase activity / ventricular system development / snRNA transcription by RNA polymerase II / CAK-ERCC2 complex / transcription factor TFIIK complex / adult heart development / transcription factor TFIIH core complex / transcription factor TFIIH holo complex / cyclin-dependent protein serine/threonine kinase activator activity / [RNA-polymerase]-subunit kinase / RNA Polymerase I Transcription Termination / cyclin-dependent protein serine/threonine kinase regulator activity / RNA Pol II CTD phosphorylation and interaction with CE during HIV infection / RNA Pol II CTD phosphorylation and interaction with CE / Formation of the Early Elongation Complex / Formation of the HIV-1 Early Elongation Complex / 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 / mRNA Capping / regulation of G1/S transition of mitotic cell cycle / RNA Polymerase I Transcription Initiation / RNA polymerase II transcribes snRNA genes / ATP-dependent activity, acting on DNA / cyclin-dependent kinase / Tat-mediated elongation of the HIV-1 transcript / cyclin-dependent protein serine/threonine kinase activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / RNA Polymerase II Transcription Elongation / cyclin-dependent protein kinase holoenzyme complex / Formation of RNA Pol II elongation complex / RNA Polymerase II Pre-transcription Events / positive regulation of smooth muscle cell proliferation / RNA polymerase II CTD heptapeptide repeat kinase activity / male germ cell nucleus / nucleotide-excision repair / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / RNA Polymerase I Promoter Escape / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / G1/S transition of mitotic cell cycle / Formation of Incision Complex in GG-NER / response to calcium ion / NoRC negatively regulates rRNA expression / Dual incision in TC-NER / Gap-filling DNA repair synthesis and ligation in TC-NER / Cyclin D associated events in G1 / fibrillar center / kinase activity / RUNX1 regulates transcription of genes involved in differentiation of HSCs / transcription by RNA polymerase II / protein kinase activity / regulation of cell cycle / protein stabilization / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / perinuclear region of cytoplasm / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytosol / cytoplasm
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, C-terminal domain 2 / Cyclin C-terminal domain / Cyclin/Cyclin-like subunit Ssn8 / Ubiquitin interacting motif ...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, C-terminal domain 2 / Cyclin C-terminal domain / Cyclin/Cyclin-like subunit Ssn8 / 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-dependent kinase 7 / Cyclin-H / CDK-activating kinase assembly factor MAT1
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 2.6 Å
AuthorsCushing VI / Greber BJ / Ali S / Lai C-F / Bevan CL / Coombes RC / Buluwela L
Funding support United Kingdom, 1 items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom)MR/V009354/1 United Kingdom
CitationJournal: To Be Published
Title: Mutation of CDK7 at a conserved residue identifies a common mechanism of acquired resistance to CDK inhibitors in cancer
Authors: Lai C-F / Cushing VI / Bevan CL / Coombes RC / Greber BJ / Buluwela L / Ali S
History
DepositionNov 27, 2024-
Header (metadata) releaseAug 20, 2025-
Map releaseAug 20, 2025-
UpdateAug 20, 2025-
Current statusAug 20, 2025Processing site: PDBe / Status: Released

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Structure visualization

Supplemental images

emd_52205.png

Downloads & links

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Map

FileDownload / File: emd_52205.map.gz / Format: CCP4 / Size: 22.2 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
AnnotationSharpened, post-processed EM map
Projections & slices

Image control

Size
Brightness
Contrast
Others
AxesZ (Sec.)Y (Row.)X (Col.)
1.15 Å/pix.
x 180 pix.
= 207.36 Å		1.15 Å/pix.
x 180 pix.
= 207.36 Å		1.15 Å/pix.
x 180 pix.
= 207.36 Å

Surface

Projections

Slices (1/3)

Slices (1/2)

Slices (2/3)

Images are generated by Spider.

Voxel sizeX=Y=Z: 1.152 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.15369065 - 0.24044624
Average (Standard dev.)0.00006583075 (±0.0062020356)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions180180180
Spacing180180180
CellA=B=C: 207.35999 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_52205_msk_1.map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Unfiltered EM half-map

Fileemd_52205_half_map_1.map
AnnotationUnfiltered EM half-map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Half map: Unfiltered EM half-map

Fileemd_52205_half_map_2.map
AnnotationUnfiltered EM half-map
Projections & Slices
AxesZYX

Projections

Slices (1/2)
Density Histograms

Histogram

Histogram (log scale)

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Sample components

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Entire : CDK-activating kinase (CAK)

EntireName: CDK-activating kinase (CAK)
Components
  • Complex: CDK-activating kinase (CAK)
    • Protein or peptide: CDK-activating kinase assembly factor MAT1
    • Protein or peptide: Cyclin-H
    • Protein or peptide: Cyclin-dependent kinase 7
  • Ligand: N-(3-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)-4-{[4-(dimethylamino)butanoyl]amino}benzamide
  • Ligand: water

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Supramolecule #1: CDK-activating kinase (CAK)

SupramoleculeName: CDK-activating kinase (CAK) / type: complex / ID: 1 / Parent: 0 / Macromolecule list: #1-#3
Details: CAK (CDK7 D97N mutant) modified by the covalent inhibitor THZ1
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 85 KDa

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Macromolecule #1: CDK-activating kinase assembly factor MAT1

MacromoleculeName: CDK-activating kinase assembly factor MAT1 / type: protein_or_peptide / ID: 1 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 10.234531 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString:
SNAPVTFSTG IKMGQHISLA PIHKLEEALY EYQPLQIETY GPHVPELEML GRLGYLNHVR AASPQDLAGG YTSSLACHRA LQDAFSGLF WQPS

UniProtKB: CDK-activating kinase assembly factor MAT1

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Macromolecule #2: Cyclin-H

MacromoleculeName: Cyclin-H / type: protein_or_peptide / ID: 2 / Number of copies: 1 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 37.721508 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: (ACE)MYHNSSQKR HWTFSSEEQL ARLRADANRK FRCKAVANGK VLPNDPVFLE PHEEMTLCKY YEKRLLEFCS VFKPAM PRS VVGTACMYFK RFYLNNSVME YHPRIIMLTC AFLACKVDEF NVSSPQFVGN LRESPLGQEK ALEQILEYEL LLIQQLN FH LIVHNPYRPF ...String:
(ACE)MYHNSSQKR HWTFSSEEQL ARLRADANRK FRCKAVANGK VLPNDPVFLE PHEEMTLCKY YEKRLLEFCS VFKPAM PRS VVGTACMYFK RFYLNNSVME YHPRIIMLTC AFLACKVDEF NVSSPQFVGN LRESPLGQEK ALEQILEYEL LLIQQLN FH LIVHNPYRPF EGFLIDLKTR YPILENPEIL RKTADDFLNR IALTDAYLLY TPSQIALTAI LSSASRAGIT MESYLSES L MLKENRTCLS QLLDIMKSMR NLVKKYEPPR SEEVAVLKQK LERCHSAELA LNVITKKRKG YEDDDYVSKK SKHEEEEWT DDDLVESL

UniProtKB: Cyclin-H

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Macromolecule #3: Cyclin-dependent kinase 7

MacromoleculeName: Cyclin-dependent kinase 7 / type: protein_or_peptide / ID: 3 / Number of copies: 1 / Enantiomer: LEVO / EC number: cyclin-dependent kinase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 39.361613 KDa
Recombinant expressionOrganism: Trichoplusia ni (cabbage looper)
SequenceString: SNAMALDVKS RAKRYEKLDF LGEGQFATVY KARDKNTNQI VAIKKIKLGH RSEAKDGINR TALREIKLLQ ELSHPNIIGL LDAFGHKSN ISLVFDFMET NLEVIIKDNS LVLTPSHIKA YMLMTLQGLE YLHQHWILHR DLKPNNLLLD ENGVLKLADF G LAKSFGSP ...String:
SNAMALDVKS RAKRYEKLDF LGEGQFATVY KARDKNTNQI VAIKKIKLGH RSEAKDGINR TALREIKLLQ ELSHPNIIGL LDAFGHKSN ISLVFDFMET NLEVIIKDNS LVLTPSHIKA YMLMTLQGLE YLHQHWILHR DLKPNNLLLD ENGVLKLADF G LAKSFGSP NRAYTHQVVT RWYRAPELLF GARMYGVGVD MWAVGCILAE LLLRVPFLPG DSDLDQLTRI FETLGTPTEE QW PDMCSLP DYVTFKSFPG IPLHHIFSAA GDDLLDLIQG LFLFNPCARI TATQALKMKY FSNRPGPTPG CQLPRPNCPV ETL KEQSNP ALAIKRKRTE ALEQGGLPKK LIF

UniProtKB: Cyclin-dependent kinase 7

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Macromolecule #4: N-(3-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)-4-{...

MacromoleculeName: N-(3-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)-4-{[4-(dimethylamino)butanoyl]amino}benzamide
type: ligand / ID: 4 / Number of copies: 1 / Formula: V0G
Molecular weightTheoretical: 568.069 Da
Chemical component information

ChemComp-V0G:
N-(3-{[5-chloro-4-(1H-indol-3-yl)pyrimidin-2-yl]amino}phenyl)-4-{[4-(dimethylamino)butanoyl]amino}benzamide

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Macromolecule #5: water

MacromoleculeName: water / type: ligand / ID: 5 / Number of copies: 59 / Formula: HOH
Molecular weightTheoretical: 18.015 Da
Chemical component information

ChemComp-HOH:
WATER

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration0.44 mg/mL
BufferpH: 7.9
Component:
ConcentrationFormulaName
200.0 mMKClPotassium chloride
2.0 mMMgCl2Magnesium chloride
20.0 mMHEPES-KOH
GridModel: UltrAuFoil R1.2/1.3 / Material: GOLD / Mesh: 300 / Support film - Material: GOLD / Support film - topology: HOLEY / Pretreatment - Type: PLASMA CLEANING / Pretreatment - Time: 50 sec.
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 278 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS KRIOS
Specialist opticsEnergy filter - Name: TFS Selectris X / Energy filter - Slit width: 10 eV
Image recordingFilm or detector model: TFS FALCON 4i (4k x 4k) / Number grids imaged: 1 / Number real images: 9043 / Average electron dose: 70.0 e/Å2
Electron beamAcceleration voltage: 300 kV / Electron source: FIELD EMISSION GUN
Electron opticsC2 aperture diameter: 50.0 µm / Illumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Cs: 2.7 mm / Nominal defocus max: 1.9000000000000001 µm / Nominal defocus min: 0.7000000000000001 µm / Nominal magnification: 215000
Sample stageSpecimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER / Cooling holder cryogen: NITROGEN
Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company

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Image processing

CTF correctionSoftware: (Name: RELION (ver. 5.0), cryoSPARC (ver. v4.4.1))
Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: EMDB MAP
EMDB ID:

17129

Final reconstructionAlgorithm: FOURIER SPACE / Resolution.type: BY AUTHOR / Resolution: 2.6 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: RELION (ver. 5.0) / Number images used: 956820
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: RELION (ver. 5.0)
Final 3D classificationNumber classes: 4 / Software - Name: RELION (ver. 5.0)

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Atomic model buiding 1

Initial modelPDB ID:

8orm


Chain - Source name: PDB / Chain - Initial model type: experimental model
RefinementSpace: REAL / Protocol: RIGID BODY FIT
Output model

PDB-9hix:
Cryo-EM structure of CAK (CDK7 D97N mutant) in complex with THZ1

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