Watanabe Mariko, Nakashima Makoto, Togano Tomiteru, Higashihara Masaaki, Watanabe Toshiki, Umezawa Kazuo, Horie Ryouichi
Department of Hematology, School of Medicine, Kitasato University, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan.
Biochem Biophys Res Commun. 2008 Nov 14;376(2):310-4. doi: 10.1016/j.bbrc.2008.08.148. Epub 2008 Sep 7.
A new NF-kappaB inhibitor dehydroxymethylepoxyquinomicin (DHMEQ) has a potential to be applied to clinical medicine as an anti-cancer and anti-inflammatory agent. DHMEQ inhibits localization of NF-kappaB in the nucleus and the inhibitory effect by DHMEQ is more potent on p50/RelA than on p50 homodimer. However, a molecular target of DHMEQ is unknown. In this study, we identified residues CEGRSAGSI, which appear in RelA (amino acids 38-46), c-Rel (28-36), and RelB (144-152), but not in p50 and p52, as a target of DHMEQ. As a possible mechanism, we propose that DHMEQ accesses CEGRSAGSI domain recognizing RSAGSI structure and directly binds to cysteine. This target domain appears to be unique among mammalian proteins. The results obtained in this study may provide better understanding of the action of DHMEQ and a key for developing a new NF-kappaB inhibitor with more potent activity.
一种新型核因子-κB抑制剂去羟甲基环氧喹霉素（DHMEQ）有潜力作为抗癌和抗炎药物应用于临床医学。DHMEQ抑制核因子-κB在细胞核内的定位，且其对p50/RelA的抑制作用比对p50同二聚体更强。然而，DHMEQ的分子靶点尚不清楚。在本研究中，我们确定了位于RelA（氨基酸38 - 46）、c-Rel（28 - 36）和RelB（144 - 152）中但不在p50和p52中的CEGRSAGSI残基是DHMEQ的靶点。作为一种可能的机制，我们提出DHMEQ通过识别RSAGSI结构进入CEGRSAGSI结构域并直接与半胱氨酸结合。该靶点结构域在哺乳动物蛋白中似乎是独特的。本研究获得的结果可能有助于更好地理解DHMEQ的作用，并为开发具有更强活性的新型核因子-κB抑制剂提供关键线索。
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