9QL1

Cryo-EM structure of the CDK11B-cyclin L2-SAP30BP bound to OTS964 (conformation 2)

Summary for 9QL1

• Entry DOI: 10.2210/pdb9ql1/pdb
• EMDB information: 53221
• Descriptor: SAP30-binding protein, Cyclin-L2, Cyclin-dependent kinase 11B, ... (5 entities in total)
• Functional Keywords: kinase, cyclin-dependent kinase, inhibitor, transcription, molecular complex, splicing
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 120320.19

Authors

McGeoch, A.J.S.,Cushing, V.I.,Cronin, N.B.,Alfieri, C.,Greber, B.J. (deposition date: 2025-03-20, release date: 2026-03-18, Last modification date: 2026-05-06)

Primary citation

McGeoch, A.J.S.,Cushing, V.I.,Roumeliotis, T.I.,Cronin, N.B.,Hearnshaw, S.J.,Choudhary, J.S.,Alfieri, C.,Greber, B.J.
Cryo-EM structures of the CDK11-cyclin L-SAP30BP complex reveal mechanisms of CDK11 regulation.
Nat Commun, 2026

PubMed Abstract: 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.

PubMed: 42034640
DOI: 10.1038/s41467-026-72329-4

Experimental method

ELECTRON MICROSCOPY (2.4 Å)