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Structure paper

TitleStructural basis of T-loop-independent recognition and activation of CDKs by the CDK-activating kinase.
Journal, issue, pagesScience, Vol. 390, Issue 6776, Page 911-917, Year 2025
Publish dateNov 27, 2025
AuthorsVictoria 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 /
PubMed AbstractCyclin-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. In this study, we determined 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 the 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.
External linksScience / PubMed:41100585 / PubMed Central
MethodsEM (single particle)
Resolution2.4 - 3.5 Å
Structure data

52758

9i9i

EMDB-52758, PDB-9i9i:
Cryo-EM structure of CAK-CDK11
Method: EM (single particle) / Resolution: 3.5 Å

EMDB-52759: Cryo-EM structure of CAK-CDK2-cyclin A2 bound to AMP-PNP (locally refined map)
Method: EM (single particle) / Resolution: 2.6 Å

52760

9i9j

EMDB-52760, PDB-9i9j:
Cryo-EM structure of CAK-CDK2 (determined in the presence of ADP-nitrate)
Method: EM (single particle) / Resolution: 3.1 Å

52761

9i9k

EMDB-52761, PDB-9i9k:
Cryo-EM structure of CAK-CDK2 (determined in the presence of ADP-AlFx)
Method: EM (single particle) / Resolution: 2.4 Å

53027

9qcv

EMDB-53027, PDB-9qcv:
Cryo-EM structure of CAK-CDK2-cyclin A2 bound to AMP-PNP
Method: EM (single particle) / Resolution: 2.5 Å

53028

9qcx

EMDB-53028, PDB-9qcx:
Cryo-EM structure of apo-CAK-CDK2-cyclin A2
Method: EM (single particle) / Resolution: 2.6 Å

54971

9skq

EMDB-54971, PDB-9skq:
Cryo-EM structure of CAK-CDK1-cyclin B1
Method: EM (single particle) / Resolution: 3.4 Å

Chemicals

ChemComp-ADP:
ADENOSINE-5'-DIPHOSPHATE / ADP, energy-carrying molecule*YM

ChemComp-MG:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-ANP:
PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER / AMP-PNP, energy-carrying molecule analogue*YM

Source
  • homo sapiens (human)
KeywordsTRANSFERASE / Complex / cell cycle / kinase

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