Abstract
The cyclin-dependent kinase CDK11 functions in transcription, mitotic progression, and mRNA splicing. Specifically, spliceosome activation during the B to Bact 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.
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Acknowledgements
We thank Teige Matthews-Palmer for help with electron microscopy, Ruth Knight for help with insect cell culture, Christopher Richardson for help with high-performance computing, and Shruti Mittal, Caroline Ewens and Rob van Montfort for support of biophysical assays. We thank Vlad Pena, Max Douglas, Jonathon Pines and Ioana Maruntel for discussions. We acknowledge the Addgene plasmid repository and depositors John Chodera, Nicholas Levinson and Markus Seeliger, from whom we obtained the human CDK2 plasmid and Jonathon Pines, from whom we obtained the human cyclin A sequence. We acknowledge Diamond and our local contact Éilís Bragginton for access and support of the cryo-EM facilities at the UK national electron Bio-Imaging Centre (eBIC), proposal BI33974 (session BI33974-9), and we acknowledge data collection at the London Consortium for High-Resolution Cryo-EM (LonCEM) facility, supported by Wellcome grant no. 206175/Z/17/Z and partner institutes. For the purpose of Open Access, the authors have applied a CC-BY public copyright license to any author accepted manuscript (AAM) version arising from this submission. B.J.G. was supported by a career development fellowship from the Medical Research Council of the UK (MR/V009354/1), and A.J.S.M. was funded by an ICR PhD studentship.
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McGeoch, A.J.S., Cushing, V.I., Roumeliotis, T.I. et al. Cryo-EM structures of the CDK11-cyclin L-SAP30BP complex reveal mechanisms of CDK11 regulation. Nat Commun (2026). https://doi.org/10.1038/s41467-026-72329-4
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DOI: https://doi.org/10.1038/s41467-026-72329-4
