Abstract：
Lens epithelium-derived growth factor (LEDGF/p75) is an epigenetic reader and attractive therapeutic target involved in HIV integration and the development of mixed lineage leukaemia (MLL1) fusion-driven leukaemia. Besides HIV integrase and the MLL1-menin complex, LEDGF/p75 interacts with various cellular proteins via its integrase binding domain (IBD). Here we present structural characterization of IBD interactions with transcriptional repressor JPO2 and domesticated transposase PogZ, and show that the PogZ interaction is nearly identical to the interaction of LEDGF/p75 with MLL1. The interaction with the IBD is maintained by an intrinsically disordered IBD-binding motif (IBM) common to all known cellular partners of LEDGF/p75. In addition, based on IBM conservation, we identify and validate IWS1 as a novel LEDGF/p75 interaction partner. Our results also reveal how HIV integrase efficiently displaces cellular binding partners from LEDGF/p75. Finally, the similar binding modes of LEDGF/p75 interaction partners represent a new challenge for the development of selective interaction inhibitors.
摘要：
晶状体上皮衍生生长因子（LEDGF/p75）是一种表观遗传学读者和有吸引力的治疗靶标，涉及HIV整合和混合谱系白血病（MLL1）融合驱动的白血病的发展。除了HIV整合酶和MLL1-menin复合物，LEDGF/p75通过其整合酶结合域(IBD)与各种细胞蛋白相互作用。在这里，我们介绍了IBD与转录抑制因子JPO2和驯化转座酶PogZ相互作用的结构表征，并显示PogZ相互作用与LEDGF/p75与MLL1的相互作用几乎相同。与IBD的相互作用由LEDGF/p75的所有已知细胞伴侣共有的固有无序IBD结合基序(IBM)维持。此外,基于IBM保护，我们鉴定并验证了IWS1是一种新型的LEDGF/p75相互作用伴侣.我们的结果还揭示了HIV整合酶如何有效地从LEDGF/p75置换细胞结合配偶体。最后,LEDGF/p75相互作用配偶体的相似结合模式代表了开发选择性相互作用抑制剂的新挑战.
