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8BU4

Structure of DDB1 bound to DS22-engaged CDK12-cyclin K

8BU4 の概要
エントリーDOI10.2210/pdb8bu4/pdb
分子名称DNA damage-binding protein 1, Cyclin-dependent kinase 12, Cyclin-K, ... (5 entities in total)
機能のキーワードkinase, cyclin, ubiquitin, degrader, ligase
由来する生物種Homo sapiens (human)
詳細
タンパク質・核酸の鎖数9
化学式量合計499406.71
構造登録者
Kozicka, Z.,Kempf, G.,Focht, V.,Thoma, N.H. (登録日: 2022-11-30, 公開日: 2023-09-13, 最終更新日: 2024-10-16)
主引用文献Kozicka, Z.,Suchyta, D.J.,Focht, V.,Kempf, G.,Petzold, G.,Jentzsch, M.,Zou, C.,Di Genua, C.,Donovan, K.A.,Coomar, S.,Cigler, M.,Mayor-Ruiz, C.,Schmid-Burgk, J.L.,Haussinger, D.,Winter, G.E.,Fischer, E.S.,Slabicki, M.,Gillingham, D.,Ebert, B.L.,Thoma, N.H.
Design principles for cyclin K molecular glue degraders.
Nat.Chem.Biol., 20:93-102, 2024
Cited by
PubMed Abstract: 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.
PubMed: 37679459
DOI: 10.1038/s41589-023-01409-z
主引用文献が同じPDBエントリー
実験手法
X-RAY DIFFRACTION (3.09 Å)
構造検証レポート
Validation report summary of 8bu4
検証レポート(詳細版)ダウンロードをダウンロード

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件を2024-12-18に公開中

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