9FMR
Structure of DDB1/Cdk12/Cyclin K with molecular glue SR-4835
Summary for 9FMR
| Entry DOI | 10.2210/pdb9fmr/pdb |
| Related | 8BU5 8P81 |
| Descriptor | DNA damage-binding protein 1, Cyclin-dependent kinase 12, Cyclin-K, ... (5 entities in total) |
| Functional Keywords | cyclin-dependent kinase, cdk, cyclin, inhibitor, sr-4835, molecular glue, transcription |
| Biological source | Homo sapiens (human) More |
| Total number of polymer chains | 9 |
| Total formula weight | 507357.32 |
| Authors | Anand, K.,Schmitz, M.,Geyer, M. (deposition date: 2024-06-07, release date: 2024-10-16, Last modification date: 2025-04-30) |
| Primary citation | Ghosh, P.,Schmitz, M.,Pandurangan, T.,Zeleke, S.T.,Chan, S.C.,Mosior, J.,Sun, L.,Palve, V.,Grassie, D.,Anand, K.,Frydman, S.,Roush, W.R.,Schonbrunn, E.,Geyer, M.,Duckett, D.,Monastyrskyi, A. Discovery and design of molecular glue enhancers of CDK12-DDB1 interactions for targeted degradation of cyclin K. Rsc Chem Biol, 6:36-55, 2024 Cited by PubMed Abstract: The CDK12 inhibitor SR-4835 promotes the proteasomal degradation of cyclin K, contingent on the presence of CDK12 and the CUL4-RBX1-DDB1 E3 ligase complex. The inhibitor displays molecular glue activity, which correlates with its enhanced ability to inhibit cell growth. This effect is achieved by facilitating the formation of a ternary complex that requires the small molecule SR-4835, CDK12, and the adaptor protein DDB1, leading to the subsequent ubiquitination and degradation of cyclin K. We have successfully solved the structure of the ternary complex, enabling the design of molecular glues that transform four different CDK12 scaffold inhibitors, including the clinical pan-CDK inhibitor dinaciclib, into cyclin K degraders. These results not only deepen our understanding of CDK12's role in cell regulation but also underscore significant progress in designing molecular glues for targeted protein degradation in cancers associated with dysregulated cyclin K activity. PubMed: 39450271DOI: 10.1039/d4cb00190g PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (3.9 Å) |
Structure validation
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