8bus

Structure of DDB1 bound to DS59-engaged CDK12-cyclin K

spinqualitylabelsall models 8bus, resolution 3.26Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 8bus is a 9 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 3.26Å Ligands: RMX, SO4, TPO Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed Molecular glue degraders are an effective therapeutic modality, but their design principles are not well understood. Recently, several unexpectedly diverse compounds were reported to deplete cyclin K by linking CDK12-cyclin K to the DDB1-CUL4-RBX1 E3 ligase. Here, to investigate how chemically dissimilar small molecules trigger cyclin K degradation, we evaluated 91 candidate degraders in structural, biophysical and cellular studies and reveal all compounds acquire glue activity via simultaneous CDK12 binding and engagement of DDB1 interfacial residues, in particular Arg928. While we identify multiple published kinase inhibitors as cryptic degraders, we also show that these glues do not require pronounced inhibitory properties for activity and that the relative degree of CDK12 inhibition versus cyclin K degradation is tuneable. We further demonstrate cyclin K degraders have transcriptional signatures distinct from CDK12 inhibitors, thereby offering unique therapeutic opportunities. The systematic structure-activity relationship analysis presented herein provides a conceptual framework for rational molecular glue design. Design principles for cyclin K molecular glue degraders.,Kozicka Z, Suchyta DJ, Focht V, Kempf G, Petzold G, Jentzsch M, Zou C, Di Genua C, Donovan KA, Coomar S, Cigler M, Mayor-Ruiz C, Schmid-Burgk JL, Haussinger D, Winter GE, Fischer ES, Slabicki M, Gillingham D, Ebert BL, Thoma NH Nat Chem Biol. 2024 Jan;20(1):93-102. doi: 10.1038/s41589-023-01409-z. Epub 2023 , Sep 7. PMID:37679459 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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