Cryo-EM structures of the CDK11-cyclin L-SAP30BP complex reveal mechanisms of CDK11 regulation

McGeoch, A. J. S.; Cushing, V. I.; Roumeliotis, T. I.; Cronin, N. B.; Hearnshaw, S. J.; Choudhary, J. S.; Alfieri, C.; Greber, B. J.

doi:10.64898/2026.03.24.713564

bioRxiv · 10.64898/2026.03.24.713564

Cryo-EM structures of the CDK11-cyclin L-SAP30BP complex reveal mechanisms of CDK11 regulation

McGeoch, A. J. S.·Cushing, V. I.·Roumeliotis, T. I.·Cronin, N. B.·Hearnshaw, S. J.·Choudhary, J. S.·Alfieri, C.·Greber, B. J.

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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 [A] 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 L2-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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McGeoch, A. J. S., Cushing, V. I., Roumeliotis, T. I., Cronin, N. B., Hearnshaw, S. J., Choudhary, J. S., Alfieri, C., Greber, B. J.. 2026-03-26. Cryo-EM structures of the CDK11-cyclin L-SAP30BP complex reveal mechanisms of CDK11 regulation. https://doi.org/10.64898/2026.03.24.713564

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