卡林
泛素连接酶
泛素
泛素蛋白连接酶类
细胞生物学
小分子
调制(音乐)
化学
生物物理学
生物化学
生物
物理
声学
基因
作者
Kenneth Wu,Robert J. DeVita,Zhen‐Qiang Pan
标识
DOI:10.1016/j.jbc.2024.105752
摘要
Cullin (CUL)-RING (Really Interesting New Gene) E3 ubiquitin (Ub) ligases (CRLs) are the largest E3 family. The E3 CRL core ligase is a sub-complex formed by the CUL C-terminal domain bound with the ROC1/RBX1 RING finger protein, which acts as a hub that mediates and organizes multiple interactions with E2, Ub, Nedd8, and the ARIH family protein, thereby resulting in Ub transfer to the E3-bound substrate. This report describes modulation of CRL-dependent ubiquitination by small molecule compounds including KH-4-43, #33 and suramin, which target the CRL core ligases. We also show that both KH-4-43 and #33 inhibit the ubiquitination of CK1α by CRL4CRBN. However, either compound’s inhibitory effect on this reaction is significantly reduced when a neddylated form of CRL4CRBN is used. On the other hand, both #33 and KH-4-43 inhibit the ubiquitination of β-catenin by CRL1β-TrCP and Nedd8-CRL1β-TrCP almost equally. Thus, neddylation of CRL1β-TrCP does not negatively impact the sensitivity to inhibition by #33 and KH-4-43. These findings suggest that the effects of neddylation to alter the sensitivity of CRL inhibition by KH-4-43/#33 is dependent upon the specific CRL type. Suramin, a compound that targets CUL’s basic canyon, can effectively inhibit CRL1/4-dependent ubiquitination regardless of neddylation status, in contrast to the results observed with KH-4-43/#33. This observed differential drug sensitivity of KH-4-43/#33 appears to echo CUL-specific Nedd8 effects on CRLs as revealed by recent high resolution structural biology efforts. The highly diversified CRL core ligase structures may provide opportunities for specific targeting by small molecule modulators.
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