9HIU

Cryo-EM structure of CDK2-cyclin A bound to a GMNC peptide

Summary for 9HIU

• Entry DOI: 10.2210/pdb9hiu/pdb
• EMDB information: 52201
• Descriptor: Cyclin-A2, Cyclin-dependent kinase 2, Geminin coiled-coil domain-containing protein 1 (3 entities in total)
• Functional Keywords: kinase, cyclin, short linear motif, cdk2, cyclin a, cell cycle
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 3
• Total formula weight: 83940.51

Authors

de Martin Garrido, N.,Ord, M.,Cushing, V.I.,Greber, B.J.,Pryciak, P.M.,Davey, N.E. (deposition date: 2024-11-27, release date: 2025-08-20, Last modification date: 2026-03-04)

Primary citation

Ord, M.,Winters, M.J.,Subbanna, M.S.,de Martin Garrido, N.,Cushing, V.I.,Kliche, J.,Benz, C.,Ivarsson, Y.,Greber, B.J.,Pryciak, P.M.,Davey, N.E.
High-throughput investigation of cyclin docking interactions reveals the complexity of motif binding determinants.
Nat Commun, 16:7622-7622, 2025

PubMed Abstract: Many regulatory protein-protein interactions depend on Short Linear Motifs (SLiMs). In the cell cycle, cyclin-CDKs recognize SLiMs to control substrate recruitment and phosphorylation timing. Here, we measure the relative binding strength of ~100,000 peptides to 11 human cyclins from five families (D, E, A, B, and F). Using a quantitative intracellular binding assay and large-scale tiled peptide screening, we identify multiple non-canonical binders unveiling a broader repertoire of cyclin docking motif types. Cryo-electron microscopy and saturation mutagenesis studies reveal distinct binding modes and sequence features governing motif recognition, binding strength, and cyclin preference. Docking motifs vary from highly selective to pan-cyclin, thereby fine-tuning the timing of CDK phosphorylation during cell cycle. Overall, these findings provide insights into the rules encoding specificity and affinity of SLiM-mediated interactions and offer a framework for understanding motif-driven protein networks across the proteome.

PubMed: 40817109
DOI: 10.1038/s41467-025-62765-z

Experimental method

ELECTRON MICROSCOPY (3.2 Å)