Cryo-EM structure of the CDK11-cyclin L-SAP30BP complex reveals mechanisms of CDK11 regulation

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. Destabilisation of cyclin L2 in the absence of SAP30BP suggests that these principles are applicable to all CDK11-cyclin L complexes. The structure of the CDK11-cyclin L2-SAP30BP complex bound to the inhibitor OTS964, a clinical, non-covalent, high-affinity CDK11 inhibitor and a comparison to OTS964-bound off-target complexes provide insight into the mechanism of OTS964 selectivity and specificity.