Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL
Identification of small-molecule inhibitors of interaction between the BH3 domain and Bcl-xL
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DOI：
10.1038/35055085
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发表时间：
2001-02-01
影响因子：
21.3
通讯作者：
Yuan, JY
中科院分区：
文献类型：
--
作者：
Degterev, A;Lugovskoy, A;Yuan, JY
为了研究 BH3 结构域在介导 Bcl-2 家族成员促凋亡和抗凋亡活性中的作用，我们鉴定了一系列抑制 Bak BH3 肽与 Bcl-x(L) 结合的新型小分子 (BH3Is)。 NMR 分析表明，BH3Is 靶向 Bcl-x(L) 的 BH3 结合口袋。抑制剂在体外和体内特异性阻断 BH3 结构域介导的 Bcl-2 家族成员之间的异二聚化并诱导细胞凋亡。我们的结果表明，BH3 依赖性异二聚化是抗凋亡 Bcl-2 家族成员的关键功能，并且是维持细胞稳态所必需的。
To study the role of the BH3 domain in mediating pro-apoptotic and anti-apoptotic activities of Bcl-2 family members, we identified a series of novel small molecules (BH3Is) that inhibit the binding of the Bak BH3 peptide to Bcl-x(L). NMR analyses revealed that BH3Is target the BH3-binding pocket of Bcl-x(L). Inhibitors specifically block the BH3-domain-mediated heterodimerization between Bcl-2 family members in vitro and in vivo and induce apoptosis. Our results indicate that BH3-dependent heterodimerization is the key function of anti-apoptotic Bcl-2 family members and is required for the maintenance of cellular homeostasis.