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TitleCryo-EM structures of the CDK11-cyclin L-SAP30BP complex reveal mechanisms of CDK11 regulation.
Journal, issue, pagesNat Commun, Year 2026
Publish dateApr 25, 2026
AuthorsAmy J S McGeoch / Victoria I Cushing / Theodoros I Roumeliotis / Nora B Cronin / Stephen J Hearnshaw / Jyoti S Choudhary / Claudio Alfieri / Basil J Greber /
PubMed AbstractThe cyclin-dependent kinase CDK11 functions in transcription, mitotic progression, and mRNA splicing. Specifically, spliceosome activation during the B to B transition depends on phosphorylation of ...The cyclin-dependent kinase CDK11 functions in transcription, mitotic progression, and mRNA splicing. Specifically, spliceosome activation during the B to B transition depends on phosphorylation of the U2 snRNP component SF3B1 by the CDK11-cyclin L-SAP30BP complex. Here, we present the structure of this spliceosome-activating CDK-cyclin complex, determined by cryogenic electron microscopy at 2.3 Å resolution. Our structure and biochemical experiments show that SAP30BP forms extensive interactions with cyclin L2, thereby stabilising it, and forms critical interactions with the C-terminal kinase lobe of CDK11 that promote complex assembly. Destabilisation of cyclin L2 in the absence of SAP30BP suggests that these principles are applicable to all CDK11-cyclin L complexes. Furthermore, we identify a pseudo-substrate sequence near the CDK11 C-terminus and provide evidence for a role of this segment in CDK11 auto-regulation. Finally, the structure of the CDK11-cyclin L-SAP30BP complex bound to the clinical high-affinity CDK11 inhibitor OTS964 and a comparison to OTS964-bound off-target complexes provide insight into the mechanism of OTS964 selectivity and specificity.
External linksNat Commun / PubMed:42034640
MethodsEM (single particle)
Resolution2.3 - 2.5 Å
Structure data

EMDB-53204, PDB-9qjj:
Cryo-EM structure of CDK2-cyclin A bound to OTS964
Method: EM (single particle) / Resolution: 2.5 Å

EMDB-53205, PDB-9qjn:
Cryo-EM structure of the human CAK bound to OTS964
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-53221, PDB-9qkt:
Cryo-EM structure of the CDK11B-cyclin L2-SAP30BP bound to OTS964 (conformation 1)
PDB-9ql1: Cryo-EM structure of the CDK11B-cyclin L2-SAP30BP bound to OTS964 (conformation 2)
Method: EM (single particle) / Resolution: 2.4 Å

EMDB-53224, PDB-9qkz:
Cryo-EM structure of CDK11B-cyclin L2-SAP30BP bound to AMP-PNP
Method: EM (single particle) / Resolution: 2.3 Å

Chemicals

ChemComp-NK3:
OTS964

ChemComp-HOH:
WATER

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

ChemComp-MG:
Unknown entry

Source
  • homo sapiens (human)
KeywordsCELL CYCLE / kinase / cyclin-dependent kinase / inhibitor / SPLICING / transcription / molecular complex

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