人源 CtBP 与底物 MTOB 复合物的晶体结构揭示了对抑制剂设计有用的活性位点特征。
Crystal structures of human CtBP in complex with substrate MTOB reveal active site features useful for inhibitor design.
机构信息
Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, MA 01605, USA.
Division of Hematology, Oncology, and Palliative Care and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA.
出版信息
FEBS Lett. 2014 May 2;588(9):1743-8. doi: 10.1016/j.febslet.2014.03.026. Epub 2014 Mar 19.
Abstract
The oncogenic corepressors C-terminal Binding Protein (CtBP) 1 and 2 harbor regulatory d-isomer specific 2-hydroxyacid dehydrogenase (d2-HDH) domains. 4-Methylthio 2-oxobutyric acid (MTOB) exhibits substrate inhibition and can interfere with CtBP oncogenic activity in cell culture and mice. Crystal structures of human CtBP1 and CtBP2 in complex with MTOB and NAD(+) revealed two key features: a conserved tryptophan that likely contributes to substrate specificity and a hydrophilic cavity that links MTOB with an NAD(+) phosphate. Neither feature is present in other d2-HDH enzymes. These structures thus offer key opportunities for the development of highly selective anti-neoplastic CtBP inhibitors.
摘要
致癌核心抑制因子 C 端结合蛋白 (CtBP)1 和 2 含有调节 d-异构体特异性 2-羟基酸脱氢酶 (d2-HDH) 结构域。4-甲基硫代 2-氧代丁酸 (MTOB) 表现出底物抑制作用，并能在细胞培养和小鼠中干扰 CtBP 的致癌活性。与 MTOB 和 NAD(+) 结合的人 CtBP1 和 CtBP2 的晶体结构揭示了两个关键特征：一个保守的色氨酸，可能有助于底物特异性，以及一个亲水腔，将 MTOB 与 NAD(+) 磷酸盐连接起来。这些特征在其他 d2-HDH 酶中均不存在。因此，这些结构为开发高度选择性的抗肿瘤 CtBP 抑制剂提供了重要机会。
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