泛素连接酶
卡林
泛素
肽
靶蛋白
信号转导衔接蛋白
蛋白质降解
细胞生物学
生物化学
DNA连接酶
化学
生物
酶
受体
基因
作者
Young-Hoon Kim,Christina Seo,Eunhye Jeon,Inchul You,Kyubin Hwang,Injae Shin,Ha‐Soon Choi,Stephen M Hinshaw,Nathanael S. Gray,Taebo Sim
标识
DOI:10.1101/2022.12.17.520883
摘要
Abstract Chemically induced protein degradation is a powerful strategy for perturbing cellular biochemistry. The predominant mechanism of action for protein degrader drugs involves induced proximity between the cellular ubiquitin conjugation machinery and the target. Unlike traditional small molecule enzyme inhibition, targeted protein degradation can clear an undesired protein from cells. We demonstrate here the use of peptide ligands for Kelch-Like Homology Domain Containing protein 2 (KLHDC2), a substrate adaptor protein and member of the cullin-2 (CUL2) ubiquitin ligase complex, for targeted protein degradation. Peptide-based bivalent compounds that can induce proximity between KLHDC2 and target proteins cause degradation of the targeted factors. The cellular activity of these compounds depends on KLHDC2 binding. This work demonstrates the utility of KLHDC2 for targeted protein degradation and exemplifies a strategy for the rational design of new peptide-based ligands useful for this purpose.
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